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Journal Cover Pharmaceuticals
  [SJR: 1.245]   [H-I: 26]   [5 followers]  Follow
  This is an Open Access Journal Open Access journal
   ISSN (Print) 1424-8247
   Published by MDPI Homepage  [157 journals]
  • Pharmaceuticals, Vol. 11, Pages 3: Antimicrobial and Antibiofilm Activity
           of UP-5, an Ultrashort Antimicrobial Peptide Designed Using Only Arginine
           and Biphenylalanine

    • Authors: Ammar Almaaytah, Mohammed Qaoud, Gubran Khalil Mohammed, Ahmad Abualhaijaa, Daniel Knappe, Ralf Hoffmann, Qosay Al-Balas
      First page: 3
      Abstract: The recent upsurge of multidrug resistant bacteria (MDRB) among global communities has become one of the most serious challenges facing health professionals and the human population worldwide. Cationic ultrashort antimicrobial peptides (USAMPs) are a promising group of molecules that meet the required criteria of novel antimicrobial drug development. UP-5, a novel penta-peptide, displayed significant antimicrobial activities against various standard and clinical isolates of MDRB. UP-5 displayed MICs values within the range of (10–15 μM) and (55–65 μM) against Gram-positive and Gram-negative bacteria, respectively. Furthermore, UP-5 displayed antibiofilm activity with minimum biofilm eradication concentration (MBEC) value as equal to twofold higher than MIC value. At the same inhibitory concentrations, UP-5 exhibited very low or negligible toxicity toward human erythrocytes and mammalian cells. Combining UP-5 with conventional antibiotics led to a synergistic or additive mode of action that resulted in the reduction of the MIC values for some of the antibiotics by 99.7% along a significant drop in MIC values of the peptide. The stability profile of UP-5 was evaluated in full mouse plasma and serum with results indicating a more stable pattern in plasma. The present study indicates that USAMPs are promising antimicrobial agents that can avoid the negative characteristics of conventional antimicrobial peptides. Additionally, USAMPs exhibit good to moderate activity against MDRB, negligible toxicity, and synergistic outcomes in combination with conventional antimicrobial agents.
      Citation: Pharmaceuticals
      PubDate: 2018-01-02
      DOI: 10.3390/ph11010003
      Issue No: Vol. 11, No. 1 (2018)
  • Pharmaceuticals, Vol. 11, Pages 4: Endolysosomal Cation Channels and
           Cancer—A Link with Great Potential

    • Authors: Christian Grimm, Karin Bartel, Angelika Vollmar, Martin Biel
      First page: 4
      Abstract: The endolysosomal system (ES) consists of lysosomes; early, late, and recycling endosomes; and autophagosomes. It is a key regulator not only of macromolecule degradation and recycling, plasma membrane repair, homeostasis, and lipid storage, but also of antigen presentation, immune defense, cell motility, cell death signaling, tumor growth, and cancer progression. In addition, it plays a critical role in autophagy, and the autophagy-lysosome pathway is intimately associated with the hallmarks of cancer, such as escaping cell death pathways, evading immune surveillance, and deregulating metabolism. The function of endolysosomes is critically dependent on both soluble and endolysosomal membrane proteins such as ion channels and transporters. Cation channels found in the ES include members of the TRP (transient receptor potential) channel superfamily, namely TRPML channels (mucolipins) as well as two-pore channels (TPCs). In recent studies, these channels have been found to play crucial roles in endolysosomal trafficking, lysosomal exocytosis, and autophagy. Mutation or loss of these channel proteins can impact multiple endolysosomal trafficking pathways. A role for TPCs in cancer cell migration and metastasis, linked to distinct defects in endolysosomal trafficking such as integrin trafficking, has been recently established. In this review, we give an overview on the function of lysosomes in cancer with a particular focus on the roles which TPCs and TRPML channels play in the ES and how this can affect cancer cells.
      Citation: Pharmaceuticals
      PubDate: 2018-01-05
      DOI: 10.3390/ph11010004
      Issue No: Vol. 11, No. 1 (2018)
  • Pharmaceuticals, Vol. 11, Pages 5: Acknowledgement to Reviewers of
           Pharmaceuticals in 2017

    • Authors: Pharmaceuticals Editorial Office
      First page: 5
      Abstract: Peer review is an essential part in the publication process, ensuring that Pharmaceuticals maintains high quality standards for its published papers[...]
      Citation: Pharmaceuticals
      PubDate: 2018-01-10
      DOI: 10.3390/ph11010005
      Issue No: Vol. 11, No. 1 (2018)
  • Pharmaceuticals, Vol. 11, Pages 6: Gastroprotective Effects of Sulphated
           Polysaccharides from the Alga Caulerpa mexicana Reducing Ethanol-Induced
           Gastric Damage

    • Authors: José Carneiro, Ticiana Holanda, Ana Quinderé, Annyta Frota, Vitória Soares, Rayane Sousa, Manuela Carneiro, Dainesy Martins, Antoniella Gomes Duarte, Norma Benevides
      First page: 6
      Abstract: The development of the gastric lesion is complex and the result of the imbalance between aggressive and protective factors, involving the generation of free radicals and disturbance in nitric oxide (NO) production. Sulphated polysaccharides (SP), from marine algae, are widely used in biotechnological and pharmaceutical areas. In this study, we evaluated the effects of SP from the green marine alga Caulerpa mexicana (Cm-SP) in ethanol-induced gastric damage models in mice. Cm-SP (2, 20, or 200 mg/kg), administered p.o., significantly reduced gastric damage, and these effects were inhibited through pretreatment with indomethacin. Cm-SP (200 mg/kg) prevented the ethanol-induced decline in glutathione and restored its normal level. Moreover, it was able to normalize the elevated thiobarbituric acid reactive substance levels. However, Cm-SP did not show any significant effects on NO2/NO3 level, when compared to the ethanol group. The pretreatment with L- NAME induced gastric mucosal damage and did not inhibit the gastroprotective effect of Cm-SP (200 mg/kg). In conclusion, the gastroprotective effects of Cm-SP in mice involve prostaglandins and reduction in the oxidative stress and are independent of NO.
      Citation: Pharmaceuticals
      PubDate: 2018-01-20
      DOI: 10.3390/ph11010006
      Issue No: Vol. 11, No. 1 (2018)
  • Pharmaceuticals, Vol. 11, Pages 7: Effects of Polymethoxyflavonoids on
           Bone Loss Induced by Estrogen Deficiency and by LPS-Dependent Inflammation
           in Mice

    • Authors: Shigeru Matsumoto, Tsukasa Tominari, Chiho Matsumoto, Shosei Yoshinouchi, Ryota Ichimaru, Kenta Watanabe, Michiko Hirata, Florian Grundler, Chisato Miyaura, Masaki Inada
      First page: 7
      Abstract: Polymethoxyflavonoids (PMFs) are a family of the natural compounds that mainly compise nobiletin, tangeretin, heptamethoxyflavone (HMF), and tetramethoxyflavone (TMF) in citrus fruits. PMFs have shown various biological functions, including anti-oxidative effects. We previously showed that nobiletin, tangeretin, and HMF all inhibited interleukin (IL)-1-mediated osteoclast differentiation via the inhibition of prostaglandin E2 synthesis. In this study, we created an original mixture of PMFs (nobiletin, tangeretin, HMF, and TMF) and examined whether or not PMFs exhibit co-operative inhibitory effects on osteoclastogenesis and bone resorption. In a coculture of bone marrow cells and osteoblasts, PMFs dose-dependently inhibited IL-1-induced osteoclast differentiation and bone resorption. The optimum concentration of PMFs was lower than that of nobiletin alone in the suppression of osteoclast differentiation, suggesting that the potency of PMFs was stronger than that of nobiletin in vitro. The oral administration of PMFs recovered the femoral bone loss induced by estrogen deficiency in ovariectomized mice. We further tested the effects of PMFs on lipopolysaccharide-induced bone resorption in mouse alveolar bone. In an ex vivo experimental model for periodontitis, PMFs significantly suppressed the bone-resorbing activity in organ cultures of mouse alveolar bone. These results indicate that a mixture of purified nobiletin, tangeretin, HMF, and TMF exhibits a co-operative inhibitory effect for the protection against bone loss in a mouse model of bone disease, suggesting that PMFs may be potential candidates for the prevention of bone resorption diseases, such as osteoporosis and periodontitis.
      Citation: Pharmaceuticals
      PubDate: 2018-01-20
      DOI: 10.3390/ph11010007
      Issue No: Vol. 11, No. 1 (2018)
  • Pharmaceuticals, Vol. 11, Pages 8: In Silico Study, Synthesis, and
           Cytotoxic Activities of Porphyrin Derivatives

    • Authors: Fransiska Kurniawan, Youhei Miura, Rahmana Emran Kartasasmita, Abdul Mutalib, Naoki Yoshioka, Daryono Hadi Tjahjono
      First page: 8
      Abstract: Five known porphyrins, 5,10,15,20-tetrakis(p-tolyl)porphyrin (TTP), 5,10,15,20-tetrakis(p-bromophenyl)porphyrin (TBrPP), 5,10,15,20-tetrakis(p-aminophenyl)porphyrin (TAPP), 5,10,15-tris(tolyl)-20-mono(p-nitrophenyl)porphyrin (TrTMNP), 5,10,15-tris(tolyl)-20-mono(p-aminophenyl)porphyrin (TrTMAP), and three novel porphyrin derivatives, 5,15-di-[bis(3,4-ethylcarboxymethylenoxy)phenyl]-10,20-di(p-tolyl)porphyrin (DBECPDTP), 5,10-di-[bis(3,4-ethylcarboxymethylenoxy)phenyl]-15,20-di-(methylpyrazole-4-yl)porphyrin (cDBECPDPzP), 5,15-di-[bis(3,4-ethylcarboxymethylenoxy)phenyl]-10,20-di-(methylpyrazole-4-yl)porphyrin (DBECPDPzP), were used to study their interaction with protein targets (in silico study), and were synthesized. Their cytotoxic activities against cancer cell lines were tested using 3-(4,5-dimetiltiazol-2-il)-2,5-difeniltetrazolium bromide (MTT) assay. The interaction of porphyrin derivatives with carbonic anhydrase IX (CAIX) and REV-ERBβ proteins were studied by molecular docking and molecular dynamic simulation. In silico study results reveal that DBECPDPzP and TrTMNP showed the highest binding interaction with REV- ERBβ and CAIX, respectively, and both complexes of DBECPDPzP-REV-ERBβ and TrTMNP-CAIX showed good and comparable stability during molecular dynamic simulation. The studied porphyrins have selective growth inhibition activities against tested cancer cells and are categorized as marginally active compounds based on their IC50.
      Citation: Pharmaceuticals
      PubDate: 2018-01-20
      DOI: 10.3390/ph11010008
      Issue No: Vol. 11, No. 1 (2018)
  • Pharmaceuticals, Vol. 11, Pages 9: Improved Intranasal Retentivity and
           Transnasal Absorption Enhancement by PEGylated Poly-l-ornithine

    • Authors: Yusuke Kamiya, Tsutomu Yamaki, Shigehiro Omori, Masaki Uchida, Kazuo Ohtake, Mitsutoshi Kimura, Hiroshi Yamazaki, Hideshi Natsume
      First page: 9
      Abstract: We reported that the introduction of polyethylene glycol (PEG) to poly-l-ornithine (PLO), which is an homopolymeric basic amino acid having absorption-enhancement ability, prolonged retention time in an in vitro inclined plate test, probably due to an increase in viscosity caused by PEGylation. The aim of the present study is to investigate whether the introduction of PEG chains to PLO improves intranasal retention and transnasal absorption in vivo. We performed intranasal administration experiments using PLO and PEG-PLO with a model drug, fluorescein isothiocyanate dextran (FD-4), in rats under closed and open systems. In the open system, transition of plasma FD-4 concentration after co-administration with unmodified PLO was low, and the area under the plasma concentration-time curve (AUC) decreased to about 60% of that in the closed system. In contrast, the AUC after co-administration with PEG-PLO in the open system was about 90% of that in the closed system, and the transition of plasma FD-4 concentration and FD-4 absorption profile were similar to those of the closed system. These findings indicate that introducing PEG chains to homopolymeric basic amino acids (HPBAAs) is a very useful method for developing a functional absorption enhancer that can exhibit an efficient in vivo absorption-enhancing effect.
      Citation: Pharmaceuticals
      PubDate: 2018-01-25
      DOI: 10.3390/ph11010009
      Issue No: Vol. 11, No. 1 (2018)
  • Pharmaceuticals, Vol. 11, Pages 10: Self-Assembled Supramolecular
           Nanoparticles Improve the Cytotoxic Efficacy of CK2 Inhibitor THN7

    • Authors: Abdelhamid Nacereddine, Andre Bollacke, Eszter Róka, Christelle Marminon, Zouhair Bouaziz, Ferenc Fenyvesi, Ildikó Bácskay, Joachim Jose, Florent Perret, Marc Le Borgne
      First page: 10
      Abstract: Since the approval of imatinib in 2001, kinase inhibitors have revolutionized cancer therapies. Inside this family of phosphotransferases, casein kinase 2 (CK2) is of great interest and numerous scaffolds have been investigated to design CK2 inhibitors. Recently, functionalized indeno[1,2-b]indoles have been revealed to have high potency against human cancer cell lines such as MCF-7 breast carcinoma and A-427 lung carcinoma. 4-Methoxy-5-isopropyl-5,6,7,8-tetrahydroindeno[1,2-b]indole-9,10-dione (THN7), identified as a potent inhibitor of CK2 (IC50 = 71 nM), was selected for an encapsulation study in order to evaluate its antiproliferative activity as THN7-loaded cyclodextrin nanoparticles. Four α-cyclodextrins (α-CDs) were selected to encapsulate THN7 and all experiments indicated that the nanoencapsulation of this CK2 inhibitor in α-CDs was successful. No additional surface-active agent was used during the nanoformulation process. Nanoparticles formed between THN7 and α-C6H13 amphiphilic derivative gave the best results in terms of encapsulation rate (% of associated drug = 35%), with a stability constant (K11) of 298 mol·L−1 and a size of 132 nm. Hemolytic activity of the four α-CDs was determined before the in cellulo evaluation and the α-C6H13 derivative gave the lowest value of hemolytic potency (HC50 = 1.93 mol·L−1). Only the THN7-loaded cyclodextrin nanoparticles showing less toxicity on human erythrocytes (α-C6H13, α-C8H17 and α-C4H9) were tested against A-427 cells. All drug-loaded nanoparticles caused more cytotoxicity against A-427 cells than THN7 alone. Based on these results, the use of amphiphilic CD nanoparticles could be considered as a drug delivery system for indeno[1,2-b]indoles, allowing an optimized bioavailability and offering perspectives for the in vivo development of CK2 inhibitors.
      Citation: Pharmaceuticals
      PubDate: 2018-01-26
      DOI: 10.3390/ph11010010
      Issue No: Vol. 11, No. 1 (2018)
  • Pharmaceuticals, Vol. 11, Pages 11: The Implication of the Brain Insulin
           Receptor in Late Onset Alzheimer’s Disease Dementia

    • Authors: Jaume Folch, Miren Ettcheto, Oriol Busquets, Elena Sánchez-López, Rubén Castro-Torres, Ester Verdaguer, Patricia Manzine, Saghar Poor, María García, Jordi Olloquequi, Carlos Beas-Zarate, Carme Auladell, Antoni Camins
      First page: 11
      Abstract: Alzheimer’s disease (AD) is progressive neurodegenerative disorder characterized by brain accumulation of the amyloid β peptide (Aβ), which form senile plaques, neurofibrillary tangles (NFT) and, eventually, neurodegeneration and cognitive impairment. Interestingly, epidemiological studies have described a relationship between type 2 diabetes mellitus (T2DM) and this pathology, being one of the risk factors for the development of AD pathogenesis. Information as it is, it would point out that, impairment in insulin signalling and glucose metabolism, in central as well as peripheral systems, would be one of the reasons for the cognitive decline. Brain insulin resistance, also known as Type 3 diabetes, leads to the increase of Aβ production and TAU phosphorylation, mitochondrial dysfunction, oxidative stress, protein misfolding, and cognitive impairment, which are all hallmarks of AD. Moreover, given the complexity of interlocking mechanisms found in late onset AD (LOAD) pathogenesis, more data is being obtained. Recent evidence showed that Aβ42 generated in the brain would impact negatively on the hypothalamus, accelerating the “peripheral” symptomatology of AD. In this situation, Aβ42 production would induce hypothalamic dysfunction that would favour peripheral hyperglycaemia due to down regulation of the liver insulin receptor. The objective of this review is to discuss the existing evidence supporting the concept that brain insulin resistance and altered glucose metabolism play an important role in pathogenesis of LOAD. Furthermore, we discuss AD treatment approaches targeting insulin signalling using anti-diabetic drugs and mTOR inhibitors.
      Citation: Pharmaceuticals
      PubDate: 2018-01-29
      DOI: 10.3390/ph11010011
      Issue No: Vol. 11, No. 1 (2018)
  • Pharmaceuticals, Vol. 11, Pages 12: Alpha-Secretase ADAM10 Regulation:
           Insights into Alzheimer’s Disease Treatment

    • Authors: Rafaela Peron, Izabela Vatanabe, Patricia Manzine, Antoni Camins, Márcia Cominetti
      First page: 12
      Abstract: ADAM (a disintegrin and metalloproteinase) is a family of widely expressed, transmembrane and secreted proteins of approximately 750 amino acids in length with functions in cell adhesion and proteolytic processing of the ectodomains of diverse cell-surface receptors and signaling molecules. ADAM10 is the main α-secretase that cleaves APP (amyloid precursor protein) in the non-amyloidogenic pathway inhibiting the formation of β-amyloid peptide, whose accumulation and aggregation leads to neuronal degeneration in Alzheimer’s disease (AD). ADAM10 is a membrane-anchored metalloprotease that sheds, besides APP, the ectodomain of a large variety of cell-surface proteins including cytokines, adhesion molecules and notch. APP cleavage by ADAM10 results in the production of an APP-derived fragment, sAPPα, which is neuroprotective. As increased ADAM10 activity protects the brain from β-amyloid deposition in AD, this strategy has been proved to be effective in treating neurodegenerative diseases, including AD. Here, we describe the physiological mechanisms regulating ADAM10 expression at different levels, aiming to propose strategies for AD treatment. We report in this review on the physiological regulation of ADAM10 at the transcriptional level, by epigenetic factors, miRNAs and/or translational and post-translational levels. In addition, we describe the conditions that can change ADAM10 expression in vitro and in vivo, and discuss how this knowledge may help in AD treatment. Regulation of ADAM10 is achieved by multiple mechanisms that include transcriptional, translational and post-translational strategies, which we will summarize in this review.
      Citation: Pharmaceuticals
      PubDate: 2018-01-29
      DOI: 10.3390/ph11010012
      Issue No: Vol. 11, No. 1 (2018)
  • Pharmaceuticals, Vol. 11, Pages 13: A Systematic Review and Meta-Analysis
           of the In Vivo Haemodynamic Effects of Δ9-Tetrahydrocannabinol

    • Authors: Salahaden Sultan, Sophie Millar, Saoirse O’Sullivan, Timothy England
      First page: 13
      Abstract: ∆9-Tetrahydrocannabinol (THC) has complex effects on the cardiovascular system. We aimed to systematically review studies of THC and haemodynamic alterations. PubMed, Medline, and EMBASE were searched for relevant studies. Changes in blood pressure (BP), heart rate (HR), and blood flow (BF) were analysed using the Cochrane Review Manager Software. Thirty-one studies met the eligibility criteria. Fourteen publications assessed BP (number, n = 541), 22 HR (n = 567), and 3 BF (n = 45). Acute THC dosing reduced BP and HR in anaesthetised animals (BP, mean difference (MD) −19.7 mmHg, p < 0.00001; HR, MD −53.49 bpm, p < 0.00001), conscious animals (BP, MD −12.3 mmHg, p = 0.0007; HR, MD −30.05 bpm, p < 0.00001), and animal models of stress or hypertension (BP, MD −61.37 mmHg, p = 0.03) and increased cerebral BF in murine stroke models (MD 32.35%, p < 0.00001). Chronic dosing increased BF in large arteries in anaesthetised animals (MD 21.95 mL/min, p = 0.05) and reduced BP in models of stress or hypertension (MD −22.09 mmHg, p < 0.00001). In humans, acute administration increased HR (MD 8.16 bpm, p < 0.00001). THC acts differently according to species and experimental conditions, causing bradycardia, hypotension and increased BF in animals; and causing increased HR in humans. Data is limited, and further studies assessing THC-induced haemodynamic changes in humans should be considered.
      Citation: Pharmaceuticals
      PubDate: 2018-01-31
      DOI: 10.3390/ph11010013
      Issue No: Vol. 11, No. 1 (2018)
  • Pharmaceuticals, Vol. 11, Pages 14: Antibiotic Persistence as a Metabolic
           Adaptation: Stress, Metabolism, the Host, and New Directions

    • Authors: Damien Cabral, Jenna Wurster, Peter Belenky
      First page: 14
      Abstract: Persistence is a phenomenon during which a small fraction of a total bacterial population survives treatment with high concentrations of antibiotics for an extended period of time. In conjunction with biofilms, antibiotic persisters represent a major cause of recalcitrant and recurring infections, resulting in significant morbidity and mortality. In this review, we discuss the clinical significance of persister cells and the central role of bacterial metabolism in their formation, specifically with respect to carbon catabolite repression, sugar metabolism, and growth regulation. Additionally, we will examine persister formation as an evolutionary strategy used to tolerate extended periods of stress and discuss some of the response mechanisms implicated in their formation. To date, the vast majority of the mechanistic research examining persistence has been conducted in artificial in vitro environments that are unlikely to be representative of host conditions. Throughout this review, we contextualize the existing body of literature by discussing how in vivo conditions may create ecological niches that facilitate the development of persistence. Lastly, we identify how the development of next-generation sequencing and other “big data” tools may enable researchers to examine persistence mechanisms within the host to expand our understanding of their clinical importance.
      Citation: Pharmaceuticals
      PubDate: 2018-02-01
      DOI: 10.3390/ph11010014
      Issue No: Vol. 11, No. 1 (2018)
  • Pharmaceuticals, Vol. 11, Pages 15: Drug Repurposing for Schistosomiasis:
           Combinations of Drugs or Biomolecules

    • Authors: Maria João Gouveia, Paul J. Brindley, Fátima Gärtner, José M. Correia da Costa, Nuno Vale
      First page: 15
      Abstract: Schistosomiasis is a major neglected tropical disease. Control of schistosomiasis currently relies on a single drug, praziquantel, and despite its efficacy against the all schistosome species that parasitize humans, it displays some problematic drawbacks and alone is ineffective in counteracting adverse pathologies associated with infection. Moreover, due to the development of the potential emergence of PZQ-resistant strains, the search for additional or alternative antischistosomal drugs have become a public health priority. The current drug discovery for schistosomiasis has been slow and uninspiring. By contrast, repurposing of existing approved drugs may offer a safe, rapid and cost-effective alternative. Combined treatment with PZQ and other drugs with different mode of action, i.e., antimalarials, shows promise results. In addition, a combination of anthelminthic drugs with antioxidant might be advantageous for modulating oxidative processes associated with schistosomiasis. Herein, we review studies dealing with combination therapies that involve PZQ and other anthelminthic drugs and/or antioxidant agents in treatment of schistosomiasis. Whereas PZQ combined with antioxidant agents might or might not interfere with anthelminthic efficacy, combinations may nonetheless ameliorate tissue damage and infection-associated complications. In fact, alone or combine with other drugs, antioxidants might be a valuable adjuvant to reduce morbidity and mortality of schistosomiasis. Therefore, attempting new combinations of anthelmintic drugs with other biomolecules such as antioxidants provides new avenues for discovery of alternatives to PZQ.
      Citation: Pharmaceuticals
      PubDate: 2018-02-05
      DOI: 10.3390/ph11010015
      Issue No: Vol. 11, No. 1 (2018)
  • Pharmaceuticals, Vol. 11, Pages 16: Vitamin E Phosphate Nucleoside
           Prodrugs: A Platform for Intracellular Delivery of Monophosphorylated

    • Authors: Richard Daifuku, Michael Koratich, Murray Stackhouse
      First page: 16
      Abstract: Vitamin E phosphate (VEP) nucleoside prodrugs are designed to bypass two mechanisms of tumor resistance to therapeutic nucleosides: nucleoside transport and kinase downregulation. Certain isoforms of vitamin E (VE) have shown activity against solid and hematologic tumors and result in chemosensitization. Because gemcitabine is one of the most common chemotherapeutics for the treatment of cancer, it was used to demonstrate the constructs utility. Four different VE isoforms were conjugated with gemcitabine at the 5′ position. Two of these were δ-tocopherol-monophosphate (MP) gemcitabine (NUC050) and δ-tocotrienol-MP gemcitabine (NUC052). NUC050 was shown to be able to deliver gemcitabine-MP intracellularly by a nucleoside transport independent mechanism. Its half-life administered IV in mice was 3.9 h. In a mouse xenograft model of non-small cell lung cancer (NSCLC) NCI-H460, NUC050 at a dose of 40 mg/kg IV qwk × 4 resulted in significant inhibition to tumor growth on days 11–31 (p < 0.05) compared to saline control (SC). Median survival was 33 days (NUC050) vs. 25.5 days (SC) ((hazard ratio) HR = 0.24, p = 0.017). Further, NUC050 significantly inhibited tumor growth compared to historic data with gemcitabine at 135 mg/kg IV q5d × 3 on days 14–41 (p < 0.05). NUC052 was administered at a dose of 40 mg/kg IV qwk × 2 followed by 50 mg/kg qwk × 2. NUC052 resulted in inhibition to tumor growth on days 14–27 (p < 0.05) and median survival was 34 days (HR = 0.27, p = 0.033). NUC050 and NUC052 have been shown to be safe and effective in a mouse xenograft of NSCLC.
      Citation: Pharmaceuticals
      PubDate: 2018-02-06
      DOI: 10.3390/ph11010016
      Issue No: Vol. 11, No. 1 (2018)
  • Pharmaceuticals, Vol. 11, Pages 17: Interactions Between Epilepsy and

    • Authors: José Jarero-Basulto, Yadira Gasca-Martínez, Martha Rivera-Cervantes, Mónica Ureña-Guerrero, Alfredo Feria-Velasco, Carlos Beas-Zarate
      First page: 17
      Abstract: Undoubtedly, one of the most interesting topics in the field of neuroscience is the ability of the central nervous system to respond to different stimuli (normal or pathological) by modifying its structure and function, either transiently or permanently, by generating neural cells and new connections in a process known as neuroplasticity. According to the large amount of evidence reported in the literature, many stimuli, such as environmental pressures, changes in the internal dynamic steady state of the organism and even injuries or illnesses (e.g., epilepsy) may induce neuroplasticity. Epilepsy and neuroplasticity seem to be closely related, as the two processes could positively affect one another. Thus, in this review, we analysed some neuroplastic changes triggered in the hippocampus in response to seizure-induced neuronal damage and how these changes could lead to the establishment of temporal lobe epilepsy, the most common type of focal human epilepsy.
      Citation: Pharmaceuticals
      PubDate: 2018-02-07
      DOI: 10.3390/ph11010017
      Issue No: Vol. 11, No. 1 (2018)
  • Pharmaceuticals, Vol. 11, Pages 18: Third International Electronic
           Conference on Medicinal Chemistry (ECMC-3)

    • Authors: Annie Mayence, Jean Jacques Vanden Eynde
      First page: 18
      Abstract: The third International Electronic Conference on Medicinal Chemistry, organized and sponsored by MDPI AG, publisher, and the journal Pharmaceuticals, took place in November 2017 on the SciForum website ( Around 300 authors from 34 different countries participated at the event, which hosted more than 70 presentations, keynotes, videos, and posters. A short description of some works presented during that scientific meeting is disclosed in this report.
      Citation: Pharmaceuticals
      PubDate: 2018-02-09
      DOI: 10.3390/ph11010018
      Issue No: Vol. 11, No. 1 (2018)
  • Pharmaceuticals, Vol. 11, Pages 19: Application of Nanoparticle Technology
           to Reduce the Anti-Microbial Resistance through β-Lactam
           Antibiotic-Polymer Inclusion Nano-Complex

    • Authors: Constain Salamanca, Cristhian Yarce, Yony Roman, Andrés Davalos, Gustavo Rivera
      First page: 19
      Abstract: Biocompatible polymeric materials with potential to form functional structures in association with different therapeutic molecules have a high potential for biological, medical and pharmaceutical applications. Therefore, the capability of the inclusion of nano-Complex formed between the sodium salt of poly(maleic acid-alt-octadecene) and a β-lactam drug (ampicillin trihydrate) to avoid the chemical and enzymatic degradation and enhance the biological activity were evaluated. PAM-18Na was produced and characterized, as reported previously. The formation of polymeric hydrophobic aggregates in aqueous solution was determined, using pyrene as a fluorescent probe. Furthermore, the formation of polymer-drug nano-complexes was characterized by Differential Scanning Calorimetry-DSC, viscometric, ultrafiltration/centrifugation assays, zeta potential and size measurements were determined by dynamic light scattering-DLS. The PAM-18Na capacity to avoid the chemical degradation was studied through stress stability tests. The enzymatic degradation was evaluated from a pure β-lactamase, while the biological degradation was determined by different β-lactamase producing Staphylococcus aureus strains. When ampicillin was associated with PAM-18Na, the half-life time in acidic conditions increased, whereas both the enzymatic degradation and the minimum inhibitory concentration decreased to a 90 and 75%, respectively. These results suggest a promissory capability of this polymer to protect the β-lactam drugs against chemical, enzymatic and biological degradation.
      Citation: Pharmaceuticals
      PubDate: 2018-02-10
      DOI: 10.3390/ph11010019
      Issue No: Vol. 11, No. 1 (2018)
  • Pharmaceuticals, Vol. 11, Pages 1: 2017: A Fruitful Year for

    • Authors: Jean Vanden Eynde
      First page: 1
      Abstract: First of all, let me wish you a healthy and wonderful year in 2018 [...]
      Citation: Pharmaceuticals
      PubDate: 2017-12-21
      DOI: 10.3390/ph11010001
      Issue No: Vol. 11, No. 1 (2017)
  • Pharmaceuticals, Vol. 11, Pages 2: Roles of Heat Shock Proteins in
           Apoptosis, Oxidative Stress, Human Inflammatory Diseases, and Cancer

    • Authors: Paul Ikwegbue, Priscilla Masamba, Babatunji Oyinloye, Abidemi Kappo
      First page: 2
      Abstract: Heat shock proteins (HSPs) play cytoprotective activities under pathological conditions through the initiation of protein folding, repair, refolding of misfolded peptides, and possible degradation of irreparable proteins. Excessive apoptosis, resulting from increased reactive oxygen species (ROS) cellular levels and subsequent amplified inflammatory reactions, is well known in the pathogenesis and progression of several human inflammatory diseases (HIDs) and cancer. Under normal physiological conditions, ROS levels and inflammatory reactions are kept in check for the cellular benefits of fighting off infectious agents through antioxidant mechanisms; however, this balance can be disrupted under pathological conditions, thus leading to oxidative stress and massive cellular destruction. Therefore, it becomes apparent that the interplay between oxidant-apoptosis-inflammation is critical in the dysfunction of the antioxidant system and, most importantly, in the progression of HIDs. Hence, there is a need to maintain careful balance between the oxidant-antioxidant inflammatory status in the human body. HSPs are known to modulate the effects of inflammation cascades leading to the endogenous generation of ROS and intrinsic apoptosis through inhibition of pro-inflammatory factors, thereby playing crucial roles in the pathogenesis of HIDs and cancer. We propose that careful induction of HSPs in HIDs and cancer, especially prior to inflammation, will provide good therapeutics in the management and treatment of HIDs and cancer.
      Citation: Pharmaceuticals
      PubDate: 2017-12-23
      DOI: 10.3390/ph11010002
      Issue No: Vol. 11, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 77: Procedures for the GMP-Compliant
           Production and Quality Control of [18F]PSMA-1007: A Next Generation
           Radiofluorinated Tracer for the Detection of Prostate Cancer

    • Authors: Jens Cardinale, René Martin, Yvonne Remde, Martin Schäfer, Antje Hienzsch, Sandra Hübner, Anna-Maria Zerges, Heike Marx, Ronny Hesse, Klaus Weber, Rene Smits, Alexander Hoepping, Marco Müller, Oliver Neels, Klaus Kopka
      First page: 77
      Abstract: Radiolabeled tracers targeting the prostate-specific membrane antigen (PSMA) have become important radiopharmaceuticals for the PET-imaging of prostate cancer. In this connection, we recently developed the fluorine-18-labelled PSMA-ligand [18F]PSMA-1007 as the next generation radiofluorinated Glu-ureido PSMA inhibitor after [18F]DCFPyL and [18F]DCFBC. Since radiosynthesis so far has been suffering from rather poor yields, novel procedures for the automated radiosyntheses of [18F]PSMA-1007 have been developed. We herein report on both the two-step and the novel one-step procedures, which have been performed on different commonly-used radiosynthesisers. Using the novel one-step procedure, the [18F]PSMA-1007 was produced in good radiochemical yields ranging from 25 to 80% and synthesis times of less than 55 min. Furthermore, upscaling to product activities up to 50 GBq per batch was successfully conducted. All batches passed quality control according to European Pharmacopoeia standards. Therefore, we were able to disclose a new, simple and, at the same time, high yielding production pathway for the next generation PSMA radioligand [18F]PSMA-1007. Actually, it turned out that the radiosynthesis is as easily realised as the well-known [18F]FDG synthesis and, thus, transferable to all currently-available radiosynthesisers. Using the new procedures, the clinical daily routine can be sustainably supported in-house even in larger hospitals by a single production batch.
      Citation: Pharmaceuticals
      PubDate: 2017-09-27
      DOI: 10.3390/ph10040077
      Issue No: Vol. 10, No. 4 (2017)
  • Pharmaceuticals, Vol. 10, Pages 78: Heparin Mimetics: Their Therapeutic

    • Authors: Shifaza Mohamed, Deirdre Coombe
      First page: 78
      Abstract: Heparin mimetics are synthetic and semi-synthetic compounds that are highly sulfated, structurally distinct analogues of glycosaminoglycans. These mimetics are often rationally designed to increase potency and binding selectivity towards specific proteins involved in disease manifestations. Some of the major therapeutic arenas towards which heparin mimetics are targeted include: coagulation and thrombosis, cancers, and inflammatory diseases. Although Fondaparinux, a rationally designed heparin mimetic, is now approved for prophylaxis and treatment of venous thromboembolism, the search for novel anticoagulant heparin mimetics with increased affinity and fewer side effects remains a subject of research. However, increasingly, research is focusing on the non-anticoagulant activities of these molecules. Heparin mimetics have potential as anti-cancer agents due to their ability to: (1) inhibit heparanase, an endoglycosidase which facilitates the spread of tumor cells; and (2) inhibit angiogenesis by binding to growth factors. The heparin mimetic, PI-88 is in clinical trials for post-surgical hepatocellular carcinoma and advanced melanoma. The anti-inflammatory properties of heparin mimetics have primarily been attributed to their ability to interact with: complement system proteins, selectins and chemokines; each of which function differently to facilitate inflammation. The efficacy of low/non-anticoagulant heparin mimetics in animal models of different inflammatory diseases has been demonstrated. These findings, plus clinical data that indicates heparin has anti-inflammatory activity, will raise the momentum for developing heparin mimetics as a new class of therapeutic agent for inflammatory diseases.
      Citation: Pharmaceuticals
      PubDate: 2017-10-02
      DOI: 10.3390/ph10040078
      Issue No: Vol. 10, No. 4 (2017)
  • Pharmaceuticals, Vol. 10, Pages 79: Orexin Receptor Multimerization versus
           Functional Interactions: Neuropharmacological Implications for Opioid and
           Cannabinoid Signalling and Pharmacogenetics

    • Authors: Miles Thompson, Takeshi Sakurai, Innocenzo Rainero, Mary Maj, Jyrki Kukkonen
      First page: 79
      Abstract: Orexins/hypocretins are neuropeptides formed by proteolytic cleavage of a precursor peptide, which are produced by neurons found in the lateral hypothalamus. The G protein-coupled receptors (GPCRs) for these ligands, the OX1 and OX2 orexin receptors, are more widely expressed throughout the central nervous system. The orexin/hypocretin system has been implicated in many pathways, and its dysregulation is under investigation in a number of diseases. Disorders in which orexinergic mechanisms are being investigated include narcolepsy, idiopathic sleep disorders, cluster headache and migraine. Human narcolepsy has been associated with orexin deficiency; however, it has only rarely been attributed to mutations in the gene encoding the precursor peptide. While gene variations within the canine OX2 gene hcrtr2 have been directly linked with narcolepsy, the majority of human orexin receptor variants are weakly associated with diseases (the idiopathic sleep disorders, cluster headache and polydipsia-hyponatremia in schizophrenia) or are of potential pharmacogenetic significance. Evidence for functional ineractions and/or heterodimerization between wild-type an variant orexin receptors and opioid and cannabinoid receptors is discussed in the context of its relevance to depression and epilepsy.
      Citation: Pharmaceuticals
      PubDate: 2017-10-08
      DOI: 10.3390/ph10040079
      Issue No: Vol. 10, No. 4 (2017)
  • Pharmaceuticals, Vol. 10, Pages 80: PARP Inhibition by Flavonoids Induced
           Selective Cell Killing to BRCA2-Deficient Cells

    • Authors: Cathy Su, Alexis Haskins, Chisato Omata, Yasushi Aizawa, Takamitsu Kato
      First page: 80
      Abstract: High consumption of dietary flavonoids might contribute to a reduction of cancer risks. Quercetin and its glycosides have PARP inhibitory effects and can induce selective cytotoxicity in BRCA2-deficient cells by synthetic lethality. We hypothesized that common flavonoids in diet naringenin, hesperetin and their glycosides have a similar structure to quercetin, which might have comparable PARP inhibitory effects, and can induce selective cytotoxicity in BRCA2-deficient cells. We utilized Chinese hamster V79 wild type, V-C8 BRCA2-deficient and its gene-complemented cells. In vitro analysis revealed that both naringenin and hesperetin present a PARP inhibitory effect. This inhibitory effect is less specific than for quercetin. Hesperetin was more cytotoxic to V79 cells than quercetin and naringenin based on colony formation assay. Quercetin and naringenin killed V-C8 cells with lower concentrations, and presented selective cytotoxicity to BRCA2-deficient cells. However, the cytotoxicity of hesperetin was similar among all three cell lines. Glycosyl flavonoids, isoquercetin and rutin as well as naringin showed selective cytotoxicity to BRCA2-deficient cells; hesperidin did not. These results suggest that flavonoids with the PARP inhibitory effect can cause synthetic lethality to BRCA2-deficient cells when other pathways are not the primary cause of death.
      Citation: Pharmaceuticals
      PubDate: 2017-10-12
      DOI: 10.3390/ph10040080
      Issue No: Vol. 10, No. 4 (2017)
  • Pharmaceuticals, Vol. 10, Pages 81: Molecular Docking and 3D-Pharmacophore
           Modeling to Study the Interactions of Chalcone Derivatives with Estrogen
           Receptor Alpha

    • Authors: Muchtaridi Muchtaridi, Hasna Syahidah, Anas Subarnas, Muhammad Yusuf, Sharon Bryant, Thierry Langer
      First page: 81
      Abstract: Tamoxifen is the most frequently used anti-estrogen adjuvant treatment for estrogen receptor-positive breast cancer. However, it is associated with an increased risk of several serious side–effects, such as uterine cancer, stroke, and pulmonary embolism. The 2′,4′-dihydroxy-6-methoxy-3,5-dimethylchalcone (ChalcEA) from plant leaves of Eugenia aquea, has been found to inhibit the proliferation of MCF-7 human breast cancer cells in a dose-dependent manner, with an IC50 of 74.5 μg/mL (250 μM). The aim of this work was to study the molecular interactions of new ChalcEA derivatives formed with the Estrogen Receptor α (ERα) using computer aided drug design approaches. Molecular docking using Autodock 4.2 was employed to explore the modes of binding of ChalcEA derivatives with ERα. The 3D structure-based pharmacophore model was derived using LigandScout 4.1 Advanced to investigate the important chemical interactions of the ERα-tamoxifen complex structure. The binding energy and the tamoxifen-pharmacophore fit score of the best ChalcEA derivative (HNS10) were −12.33 kcal/mol and 67.07 kcal/mol, respectively. The HNS10 interacted with Leu346, Thr347, Leu349, Ala350, Glu353, Leu387, Met388, Leu391, Arg394, Met421, and Leu525. These results suggest that the new ChalcEA derivatives could serve as the lead compound for potent ERα inhibitor in the fight against breast cancer.
      Citation: Pharmaceuticals
      PubDate: 2017-10-16
      DOI: 10.3390/ph10040081
      Issue No: Vol. 10, No. 4 (2017)
  • Pharmaceuticals, Vol. 10, Pages 82: Electrographic Changes Accompanying
           Recurrent Seizures under Ketogenic Diet Treatment

    • Authors: Chiara Lucchi, Maddalena Marchiò, Elisa Caramaschi, Carmela Giordano, Rocco Giordano, Azzurra Guerra, Giuseppe Biagini
      First page: 82
      Abstract: The ketogenic diet (KD) is increasingly used to treat epilepsy refractory to antiepileptic drugs and other neurological disorders. In animal models, the KD was found to increase the threshold to seizures induced by different convulsive stimulations. However, in models in which suprathreshold stimuli were used, a paradoxical seizure worsening was consistently observed in KD-fed animals. To better define this phenomenon, we characterized the electrographic response to seizures induced in mice which were treated with the KD, and then corneally stimulated at 6-Hz in four different sessions. We also evaluated the electroencephalogram (EEG) in three patients in which the KD was associated with a paradoxical worsening of epileptic seizures. Although seizures were initially less severe, a remarkable prolongation of the electrographic response was observed in mice receiving the KD from the second session of 6-Hz corneal stimulation and onwards. The EEG was also markedly altered in the presence of progressive seizure aggravation observed in children treated with the KD, specifically one affected by Lennox–Gastaut syndrome and two by type I lissencephaly,. These results suggest that when seizures are induced or recur because of resistance to therapeutic interventions, the KD may change the EEG by potentiating the electrographic epileptic activity.
      Citation: Pharmaceuticals
      PubDate: 2017-10-20
      DOI: 10.3390/ph10040082
      Issue No: Vol. 10, No. 4 (2017)
  • Pharmaceuticals, Vol. 10, Pages 83: Systemic Interleukin-4 Administration
           after Spinal Cord Injury Modulates Inflammation and Promotes

    • Authors: Rui Lima, Susana Monteiro, José Lopes, Pedro Barradas, Natália Vasconcelos, Eduardo Gomes, Rita Assunção-Silva, Fábio Teixeira, Mónica Morais, Nuno Sousa, António Salgado, Nuno Silva
      First page: 83
      Abstract: Traumatic spinal cord injury (SCI) causes dramatic disability and dysfunction in the motor, sensory and autonomic systems. The severe inflammatory reaction that occurs after SCI is strongly associated with further tissue damage. As such, immunomodulatory strategies have been developed, aimed at reducing inflammation, but also at shaping the immune response in order to protect, repair and promote regeneration of spared neural tissue. One of those promising strategies is the intraspinal administration of the cytokine interleukin-4 (IL-4) that was shown to promote a phenotype on specific immune cells associated with neuroprotection and repair. In this work, we evaluated if a systemic delivery of IL-4 for a 7-days period was also capable of promoting neuroprotection after SCI by analyzing different neural cells populations and motor recovery. IL-4 treatment promoted an elevation of the anti-inflammatory cytokine IL-10 in the serum both at 24 h and 7 days after injury. Locally, treatment with IL-4 led to a reduction on cells expressing markers associated with inflammation, CD11b/c and iNOS. Importantly, IL-4 treatment increased the neuronal markers βIII-tubulin and NeuN, and the oligodendrocyte marker O4, suggesting a neuroprotective effect. Moreover, 100% of the animals treated with IL-4 were able to recover weight support against only 33% of saline treated animals. Overall, these results show that systemic administration of IL-4 positively impacts different aspects of spinal cord injury, creating a more favorable environment for recovery to take place.
      Citation: Pharmaceuticals
      PubDate: 2017-10-24
      DOI: 10.3390/ph10040083
      Issue No: Vol. 10, No. 4 (2017)
  • Pharmaceuticals, Vol. 10, Pages 84: Acorenone B: AChE and BChE Inhibitor
           as a Major Compound of the Essential Oil Distilled from the Ecuadorian
           Species Niphogeton dissecta (Benth.) J.F. Macbr

    • Authors: James Calva, Nicole Bec, Gianluca Gilardoni, Christian Larroque, Luis Cartuche, Carlo Bicchi, José Montesinos
      First page: 84
      Abstract: This study investigated the chemical composition, physical proprieties, biological activity, and enantiomeric analysis of the essential oil from the aerial parts of Niphogeton dissecta (culantrillo del cerro) from Ecuador, obtained by steam distillation. The qualitative and quantitative analysis of the essential oil was realized by gas chromatographic and spectroscopic techniques (GC-MS and GC-FID). Acorenone B was identified by GC-MS and NMR experiments. The enantiomeric distribution of some constituents has been assessed by enantio-GC through the use of a chiral cyclodextrin-based capillary column. We identified 41 components that accounted for 96.46% of the total analyzed, the major components were acorenone B (41.01%) and (E)-β-ocimene (29.64%). The enantiomeric ratio of (+)/(−)-β-pinene was 86.9:13.1, while the one of (+)/(−)-sabinene was 80.9:19.1. The essential oil showed a weak inhibitory activity, expressed as Minimal Inhibitory Concentration (MIC), against Enterococcus faecalis (MIC 10 mg/mL) and Staphylococcus aureus (MIC 5 mg/mL). Furthermore, it inhibited butyrylcholinesterase with an IC50 value of 11.5 μg/mL. Pure acorenone B showed inhibitory activity against both acetylcholinesterase and butyrylcholinesterase, with IC50 values of 40.8 μg/mL and 10.9 μg/mL, respectively.
      Citation: Pharmaceuticals
      PubDate: 2017-10-31
      DOI: 10.3390/ph10040084
      Issue No: Vol. 10, No. 4 (2017)
  • Pharmaceuticals, Vol. 10, Pages 85: Neurochemical Changes and c-Fos
           Mapping in the Brain after Carisbamate Treatment of Rats Subjected to
           Lithium–Pilocarpine-Induced Status Epilepticus

    • Authors: José Marques-Carneiro, Astrid Nehlig, Jean-Christophe Cassel, Eduardo Castro-Neto, Julia Litzahn, Anne Pereira de Vasconcelos, Maria Naffah-Mazacoratti, Maria Fernandes
      First page: 85
      Abstract: The administration of lithium–pilocarpine (LiPilo) in adult rats is a validated model reproducing the main clinical and neuropathological features of temporal lobe epilepsy (TLE). Previous studies have shown that carisbamate (CRS) has the property of modifying epileptogenesis in this model. When treated with CRS, about 50% of rats undergoing LiPilo status epilepticus (SE) develop non-convulsive seizures (NCS) instead of convulsive ones (commonly observed in TLE). The goal of this work was to determine some of the early changes that occur after CRS administration, as they could be involved in the insult- and epileptogenesis-modifying effects of CRS. Thus, we performed high-performance liquid chromatography (HPLC) to quantify levels of amino acids and monoamines, and c-Fos immunohistochemical labeling to map cerebral activation during seizures. Comparing rats treated one hour after SE onset with saline (CT), CRS, or diazepam (DZP), HPLC showed that 4 h after SE onset, dopamine (DA), norepinephrine (NE), and GABA levels were normal, whereas serotonin levels were increased. Using c-Fos labeling, we demonstrated increased activity in thalamic mediodorsal (MD) and laterodorsal (LD) nuclei in rats treated with CRS. In summary, at early times, CRS seems to modulate excitability by acting on some monoamine levels and increasing activity of MD and LD thalamic nuclei, suggesting a possible involvement of these nuclei in insult- and/or epileptogenesis-modifying effects of CRS.
      Citation: Pharmaceuticals
      PubDate: 2017-11-01
      DOI: 10.3390/ph10040085
      Issue No: Vol. 10, No. 4 (2017)
  • Pharmaceuticals, Vol. 10, Pages 86: Essential Oils and Antifungal Activity

    • Authors: Filomena Nazzaro, Florinda Fratianni, Raffaele Coppola, Vincenzo De Feo
      First page: 86
      Abstract: Since ancient times, folk medicine and agro-food science have benefitted from the use of plant derivatives, such as essential oils, to combat different diseases, as well as to preserve food. In Nature, essential oils play a fundamental role in protecting the plant from biotic and abiotic attacks to which it may be subjected. Many researchers have analyzed in detail the modes of action of essential oils and most of their components. The purpose of this brief review is to describe the properties of essential oils, principally as antifungal agents, and their role in blocking cell communication mechanisms, fungal biofilm formation, and mycotoxin production.
      Citation: Pharmaceuticals
      PubDate: 2017-11-02
      DOI: 10.3390/ph10040086
      Issue No: Vol. 10, No. 4 (2017)
  • Pharmaceuticals, Vol. 10, Pages 87: Synthesis and In Vitro Cytotoxicity of
           the 4-(Halogenoanilino)-6-bromoquinazolines and Their 6-(4-Fluorophenyl)
           Substituted Derivatives as Potential Inhibitors of Epidermal Growth Factor
           Receptor Tyrosine Kinase

    • Authors: Malose Mphahlele, Hugues Paumo, Yee Choong
      First page: 87
      Abstract: Series of the 2-unsubstituted and 2-(4-chlorophenyl)–substituted 4-anilino-6-bromoquinazolines and their 6-(4-fluorophenyl)–substituted derivatives were evaluated for in vitro cytotoxicity against MCF-7 and HeLa cells. The 2-unsubstituted 4-anilino-6-bromoquinazolines lacked activity, whereas most of their 2-(4-chlorophenyl) substituted derivatives were found to exhibit significant cytotoxicity and selectivity against HeLa cells. Replacement of bromine with 4-fluorophenyl group for the 2-unsubstituted 4-anilinoquinazolines resulted in superior activity against HeLa cells compared to Gefitinib. The presence of a 4-fluorophenyl group in the 2-(4-chlorophenyl) substituted derivatives led to increased cytotoxicity against HeLa cells, except for the 3-chloroanilino derivative. The most active compounds, namely, 3g, 3l, and 4l, were found to exhibit a moderate to significant inhibitory effect against epidermal growth factor receptor tyrosine kinase (EGFR-TK). The EGFR molecular docking model suggested that these compounds are nicely bound to the region of EGFR.
      Citation: Pharmaceuticals
      PubDate: 2017-11-20
      DOI: 10.3390/ph10040087
      Issue No: Vol. 10, No. 4 (2017)
  • Pharmaceuticals, Vol. 10, Pages 88: Amorphous Solid Dispersion of
           Epigallocatechin Gallate for Enhanced Physical Stability and Controlled

    • Authors: Yizheng Cao, Jing Teng, Jon Selbo
      First page: 88
      Abstract: Epigallocatechin gallate (EGCG) has been recognized as the most prominent green tea extract due to its healthy influences. The high instability and low bioavailability, however, strongly limit its utilization in food and drug industries. This work, for the first time, develops amorphous solid dispersion of EGCG to enhance its bioavailability and physical stability. Four commonly used polymeric excipients are found to be compatible with EGCG in water-dioxane mixtures via a stepwise mixing method aided by vigorous mechanical interference. The dispersions are successfully generated by lyophilization. The physical stability of the dispersions is significantly improved compared to pure amorphous EGCG in stress condition (elevated temperature and relative humidity) and simulated gastrointestinal tract environment. From the drug release tests, one of the dispersions, EGCG-Soluplus® 50:50 (w/w) shows a dissolution profile that only 50% EGCG is released in the first 20 min, and the remains are slowly released in 24 h. This sustained release profile may open up new possibilities to increase EGCG bioavailability via extending its elimination time in plasma.
      Citation: Pharmaceuticals
      PubDate: 2017-11-09
      DOI: 10.3390/ph10040088
      Issue No: Vol. 10, No. 4 (2017)
  • Pharmaceuticals, Vol. 10, Pages 89: Propagation of Fibrillar Structural
           Forms in Proteins Stopped by Naturally Occurring Short Polypeptide Chain

    • Authors: Irena Roterman, Mateusz Banach, Leszek Konieczny
      First page: 89
      Abstract: Amyloids characterized by unbounded growth of fibrillar structures cause many pathological processes. Such unbounded propagation is due to the presence of a propagating hydrophobicity field around the fibril’s main axis, preventing its closure (unlike in globular proteins). Interestingly, similar fragments, commonly referred to as solenoids, are present in many naturally occurring proteins, where their propagation is arrested by suitably located “stopper” fragments. In this work, we analyze the distribution of hydrophobicity in solenoids and in their corresponding “stoppers” from the point of view of the fuzzy oil drop model (called FOD in this paper). This model characterizes the unique linear propagation of local hydrophobicity in the solenoid fragment and allows us to pinpoint “stopper” sequences, where local hydrophobicity quite closely resembles conditions encountered in globular proteins. Consequently, such fragments perform their function by mediating entropically advantageous contact with the water environment. We discuss examples of amyloid-like structures in solenoids, with particular attention to “stop” segments present in properly folded proteins found in living organisms.
      Citation: Pharmaceuticals
      PubDate: 2017-11-16
      DOI: 10.3390/ph10040089
      Issue No: Vol. 10, No. 4 (2017)
  • Pharmaceuticals, Vol. 10, Pages 91: A Triphenylphosphonium-Functionalized
           Mitochondriotropic Nanocarrier for Efficient Co-Delivery of Doxorubicin
           and Chloroquine and Enhanced Antineoplastic Activity

    • Authors: Katerina Panagiotaki, Zili Sideratou, Spiros Vlahopoulos, Maria Paravatou-Petsotas, Michael Zachariadis, Nikolas Khoury, Vassilis Zoumpourlis, Dimitris Tsiourvas
      First page: 91
      Abstract: Drug delivery systems that target subcellular organelles and, in particular, mitochondria are considered to have great potential in treating disorders that are associated with mitochondrial dysfunction, including cancer or neurodegenerative diseases. To this end, a novel hyperbranched mitochondriotropic nanocarrier was developed for the efficient co-delivery of two different (both in chemical and pharmacological terms) bioactive compounds. The carrier is based on hyperbranched poly(ethyleneimine) functionalized with triphenylphosphonium groups that forms ~100 nm diameter nanoparticles in aqueous media and can encapsulate doxorubicin (DOX), a well-known anti-cancer drug, and chloroquine (CQ), a known chemosensitizer with arising potential in anticancer medication. The anticancer activity of this system against two aggressive DOX-resistant human prostate adenocarcinoma cell lines and in in vivo animal studies was assessed. The co-administration of encapsulated DOX and CQ leads to improved cell proliferation inhibition at extremely low DOX concentrations (0.25 μΜ). In vivo experiments against DU145 human prostate cancer cells grafted on immunodeficient mice resulted in tumor growth arrest during the three-week administration period and no pervasive side effects. The findings put forward the potential of such targeted low dose combination treatments as a therapeutic scheme with minimal adverse effects.
      Citation: Pharmaceuticals
      PubDate: 2017-11-21
      DOI: 10.3390/ph10040091
      Issue No: Vol. 10, No. 4 (2017)
  • Pharmaceuticals, Vol. 10, Pages 93: Early Gabapentin Treatment during the
           Latency Period Increases Convulsive Threshold, Reduces Microglial
           Activation and Macrophage Infiltration in the Lithium-Pilocarpine Model of

    • Authors: Alicia Rossi, Veronica Murta, Jerónimo Auzmendi, Alberto Ramos
      First page: 93
      Abstract: The lithium-pilocarpine model of epilepsy reproduces several features of temporal lobe epilepsy in humans, including the chronological timeline of an initial latency period followed by the development of spontaneous seizures. Epilepsy therapies in humans are implemented, as a rule, after the onset of the spontaneous seizures. We here studied the potential effect on epileptogenesis of starting an early treatment during the latency period, in order to prevent the development of spontaneous seizures. Adult male Wistar rats were treated with 3 mEq/kg LiCl, and 20 h later 30 mg/kg pilocarpine. Once status epilepticus (SE) was achieved, it was allowed to last for 20 min, and then motor seizures were controlled with the administration of 20 mg/kg diazepam. At 1DPSE (DPSE, days post-status epilepticus), animals started to receive 400 mg/kg/day gabapentin or saline for 4 days. At 5DPSE, we observed that SE induced an early profuse microglial and astroglial reactivity, increased synaptogenic trombospondin-1 expression and reduced AQP4 expression in astroglial ending feet. Blood brain barrier (BBB) integrity seemed to be compromised, as infiltrating NG2+ macrophages and facilitated access to the CNS was observed by transplanting eGFP+ blood cells and bone marrow-derived progenitors in the SE animals. The early 4-day gabapentin treatment successfully reduced microglial cell reactivity and blood-borne cell infiltration, without significantly altering the mRNA of proinflammatory cytokines IL-1β and TNFα immediately after the treatment. After 21DSPE, another group of animals that developed SE and received 4 days of gabapentin treatment, were re-exposed to subconvulsive accumulative doses of pilocarpine (10 mg/kg/30 min) and were followed by recording the Racine scale reached. Early 4-day gabapentin treatment reduced the Racine scale reached by the animals, reduced animal mortality, and reduced the number of animals that achieved SE (34% vs. 72%). We conclude that early gabapentin treatment following SE, during the latency period, is able to reduce neuroinflammation and produces a persistent effect that limits seizures and increases convulsive threshold, probably by restricting microglial reactivity and spurious synaptogenesis.
      Citation: Pharmaceuticals
      PubDate: 2017-11-28
      DOI: 10.3390/ph10040093
      Issue No: Vol. 10, No. 4 (2017)
  • Pharmaceuticals, Vol. 10, Pages 94: 31ièmes Journées Franco-Belges de
           Pharmacochimie: Meeting Report

    • Authors: Raphaël Frédérick, Lionel Pochet, Pascal De Tullio, François Dufrasne
      First page: 94
      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. s of plenary lectures, oral communications, and posters presented during the meeting are collected in this report.
      Citation: Pharmaceuticals
      PubDate: 2017-12-04
      DOI: 10.3390/ph10040094
      Issue No: Vol. 10, No. 4 (2017)
  • Pharmaceuticals, Vol. 10, Pages 95: Microglia M2A Polarization as
           Potential Link between Food Allergy and Autism Spectrum Disorders

    • Authors: Hans Kalkman, Dominik Feuerbach
      First page: 95
      Abstract: Atopic diseases are frequently co-morbid with autism spectrum disorders (ASD). Allergic responses are associated with an activation of mast cells, innate lymphoid cells, and Th2 cells. These cells produce type-2 cytokines (IL4 and IL13), which stimulate microglia and macrophages to adopt a phenotype referred to as ‘alternative activation’ or ‘M2A’. M2A-polarized macrophages and microglia play a physiological role in tissue repair by secreting growth factors such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1. In ASD there is evidence for increased type-2 cytokines, microglia activation, M2A polarization, and increased levels of growth factors. In neurons, these growth factors drive a signal transduction pathway that leads to activation of the enzyme mammalian Target of Rapamycin (mTOR), and thereby to the inhibition of autophagy. Activation of mTOR is an effect that is also common to several of the genetic forms of autism. In the central nervous system, redundant synapses are removed via an autophagic process. Activation of mTOR would diminish the pruning of redundant synapses, which in the context of ASD is likely to be undesired. Based on this line of reasoning, atopic diseases like food allergy, eczema or asthma would represent risk factors for autism spectrum disorders.
      Citation: Pharmaceuticals
      PubDate: 2017-12-09
      DOI: 10.3390/ph10040095
      Issue No: Vol. 10, No. 4 (2017)
  • Pharmaceuticals, Vol. 10, Pages 96: Biodegradable Scaffolds for Bone

    • Authors: Rossella Dorati, Antonella DeTrizio, Tiziana Modena, Bice Conti, Francesco Benazzo, Giulia Gastaldi, Ida Genta
      First page: 96
      Abstract: A great deal of research is ongoing in the area of tissue engineering (TE) for bone regeneration. A possible improvement in restoring damaged tissues involves the loading of drugs such as proteins, genes, growth factors, antibiotics, and anti-inflammatory drugs into scaffolds for tissue regeneration. This mini-review is focused on the combination of the local delivery of antibiotic agents with bone regenerative therapy for the treatment of a severe bone infection such as osteomyelitis. The review includes a brief explanation of scaffolds for bone regeneration including scaffolds characteristics and types, a focus on severe bone infections (especially osteomyelitis and its treatment), and a literature review of local antibiotic delivery by the combination of scaffolds and drug-delivery systems. Some examples related to published studies on gentamicin sulfate-loaded drug-delivery systems combined with scaffolds are discussed, and future perspectives are highlighted.
      Citation: Pharmaceuticals
      PubDate: 2017-12-12
      DOI: 10.3390/ph10040096
      Issue No: Vol. 10, No. 4 (2017)
  • Pharmaceuticals, Vol. 10, Pages 97: 25th Conference of GP2A

    • Authors: Michael D. Threadgill, Susan E. Matthews, Francesca Giuntini
      First page: 97
      Abstract: The 25th Conference of GP2A was held on 31 August and 1 September 2017 in Liverpool, UK, with the aim of exchange of ideas and experience, particularly amongst young medicinal chemists. Topics included bioactive compounds from plants and lichens, and design and development of drugs. s of invited lectures, proffered oral presentations, flash presentations and posters presented during the meeting are collected in this report.
      Citation: Pharmaceuticals
      PubDate: 2017-12-14
      DOI: 10.3390/ph10040097
      Issue No: Vol. 10, No. 4 (2017)
  • Pharmaceuticals, Vol. 10, Pages 98: Unexpected Binding Mode of a Potent
           Indeno[1,2-b]indole-Type Inhibitor of Protein Kinase CK2 Revealed by
           Complex Structures with the Catalytic Subunit CK2α and Its Paralog

    • Authors: Jennifer Hochscherf, Dirk Lindenblatt, Benedict Witulski, Robin Birus, Dagmar Aichele, Christelle Marminon, Zouhair Bouaziz, Marc Le Borgne, Joachim Jose, Karsten Niefind
      First page: 98
      Abstract: Protein kinase CK2, a member of the eukaryotic protein kinase superfamily, is associated with cancer and other human pathologies and thus an attractive drug target. The indeno[1,2-b]indole scaffold is a novel lead structure to develop ATP-competitive CK2 inhibitors. Some indeno[1,2-b]indole-based CK2 inhibitors additionally obstruct ABCG2, an ABC half transporter overexpressed in breast cancer and co-responsible for drug efflux and resistance. Comprehensive derivatization studies revealed substitutions of the indeno[1,2-b]indole framework that boost either the CK2 or the ABCG2 selectivity or even support the dual inhibition potential. The best indeno[1,2-b]indole-based CK2 inhibitor described yet (IC50 = 25 nM) is 5-isopropyl-4-(3-methylbut-2-enyl-oxy)-5,6,7,8-tetrahydroindeno[1,2-b]indole-9,10-dione (4p). Herein, we demonstrate the membrane permeability of 4p and describe co-crystal structures of 4p with CK2α and CK2α′, the paralogs of human CK2 catalytic subunit. As expected, 4p occupies the narrow, hydrophobic ATP site of CK2α/CK2α′, but surprisingly with a unique orientation: its hydrophobic substituents point towards the solvent while its two oxo groups are hydrogen-bonded to a hidden water molecule. An equivalent water molecule was found in many CK2α structures, but never as a critical mediator of ligand binding. This unexpected binding mode is independent of the interdomain hinge/helix αD region conformation and of the salt content in the crystallization medium.
      Citation: Pharmaceuticals
      PubDate: 2017-12-13
      DOI: 10.3390/ph10040098
      Issue No: Vol. 10, No. 4 (2017)
  • Pharmaceuticals, Vol. 10, Pages 99: Convenient Preparation of 18F-Labeled
           Peptide Probes for Potential Claudin-4 PET Imaging

    • Authors: Lucia Feni, M. Omrane, Moritz Fischer, Boris Zlatopolskiy, Bernd Neumaier, Ines Neundorf
      First page: 99
      Abstract: Since pancreatic cancer is often diagnosed in a late state of cancer development, diagnostic opportunities allowing early disease detection are highly sought after. As such, cancer expression of claudin proteins is markedly dysregulated, making it an attractive target for molecular imaging like positron emission tomography (PET). Claudins are a family of transmembrane proteins that have a pivotal role as members of the tight junctions. In particular, claudin-3 and claudin-4 are frequently overexpressed in pancreatic cancer. 18F-Labeled claudin selective peptides would provide access to a novel kind of imaging tools for pancreatic cancer. In this work we describe the synthesis of the first 18F-labeled probes potentially suitable for PET imaging of claudin-4 expression. These probes were prepared using oxime ligation of 5-[18F]fluoro-5-deoxyribose (5-[18F]FDR) to claudin selective peptides. As a proof-of-principle, one of them, 5-[18F]FDR-Clone 27, was isolated in >98% radiochemical purity and in 15% radiochemical yield (EOB) within 98 min, and with a molar activity of 4.0 GBq/μmol (for 30 MBq of tracer). Moreover, we present first biological data for the prepared 5-FDR-conjugates. These tracers could pave the way for an early diagnosis of pancreatic tumor, and thus improve the outcome of anticancer therapy.
      Citation: Pharmaceuticals
      PubDate: 2017-12-18
      DOI: 10.3390/ph10040099
      Issue No: Vol. 10, No. 4 (2017)
  • Pharmaceuticals, Vol. 10, Pages 58: Individual and Combined Effects of
           Engineered Peptides and Antibiotics on Pseudomonas aeruginosa Biofilms

    • Authors: Biswajit Mishra, Guangshun Wang
      First page: 58
      Abstract: Pseudomonas aeruginosa is involved in a variety of difficult-to-treat infections frequently due to biofilm formation. To identify useful antibiofilm strategies, this article evaluated efficacy of two newly engineered cationic antimicrobial peptides (17BIPHE2 and DASamP2), traditional antibiotics, and their combinations against biofilms at different stages. 17BIPHE2 is designed based on the 3D structure of human cathelicidin LL-37 and DASamP2 is derived from database screening. While both peptides show effects on bacterial adhesion, biofilm formation, and preformed biofilms, select antibiotics only inhibit biofilm formation, probably due to direct bacterial killing. In addition, the time dependence of biofilm formation and treatment in a static in vitro biofilm model was also studied. The initial bacterial inoculum determines the peptide concentration needed to inhibit biofilm growth. When the bacterial growth time is less than 8 h, the biomass in the wells can be dispersed by either antibiotics alone or peptides alone. However, nearly complete biofilm disruption can be achieved when both the peptide and antibiotics are applied. Our results emphasize the importance of antibiofilm peptides, early treatment using monotherapy, and the combination therapy for already formed biofilms of P. aeruginosa.
      PubDate: 2017-06-25
      DOI: 10.3390/ph10030058
      Issue No: Vol. 10, No. 3 (2017)
  • Pharmaceuticals, Vol. 10, Pages 59: Precipitation and Neutralization of
           Heparin from Different Sources by Protamine Sulfate

    • Authors: John Hogwood, Barbara Mulloy, Elaine Gray
      First page: 59
      Abstract: Current therapeutic unfractionated heparin available in Europe and US is of porcine mucosal origin. There is now interest, specifically in the US, to use bovine mucosa as an additional source for the production of heparin. The anticoagulant action of heparin can be neutralized by protamine sulfate, and in this study the ability of protamine to bind and neutralize the anticoagulant activities of heparin from porcine mucosa, bovine mucosa and bovine lung were assessed. Protamine sulfate was able to bind and precipitate similar amounts of heparins from different sources on a mass basis. However, differential amounts of anticoagulant activities were neutralized by protamine sulfate, with neutralization of porcine mucosa more effective than for bovine lung and bovine mucosa. For all heparins, potentiation of thrombin inhibition by antithrombin and heparin cofactor II was preferentially neutralized over antithrombin-mediated inhibition of factor Xa or plasma clotting time. Whole blood thromboelastography showed that neutralization by protamine sulfate was more effective than the antithrombin dependent thrombin inhibition assays indicated. While there was no absolute correlation between average or peak molecular weight of heparin samples and neutralization of anticoagulant activity, correlation was observed between proportions of material with high affinity to antithrombin, specific activities and neutralization of activity.
      PubDate: 2017-07-02
      DOI: 10.3390/ph10030059
      Issue No: Vol. 10, No. 3 (2017)
  • Pharmaceuticals, Vol. 10, Pages 60: Neuroprotective Effects of
           β-Caryophyllene against Dopaminergic Neuron Injury in a Murine Model of
           Parkinson’s Disease Induced by MPTP

    • Authors: Juan Viveros-Paredes, Rocio González-Castañeda, Juerg Gertsch, Veronica Chaparro-Huerta, Rocio López-Roa, Eduardo Vázquez-Valls, Carlos Beas-Zarate, Antoni Camins-Espuny, Mario Flores-Soto
      First page: 60
      Abstract: Parkinson’s disease (PD) is one of the most common neurodegenerative disorders and is characterized by the loss of dopaminergic neurons in the substantia nigra (SN). Although the causes of PD are not understood, evidence suggests that its pathogenesis is associated with oxidative stress and inflammation. Recent studies have suggested a protective role of the cannabinoid signalling system in PD. β-caryophyllene (BCP) is a natural bicyclic sesquiterpene that is an agonist of the cannabinoid type 2 receptor (CB2R). Previous studies have suggested that BCP exerts prophylactic and/or curative effects against inflammatory bowel disease through its antioxidative and/or anti-inflammatory action. The present study describes the neuroprotective effects of BCP in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced murine model of PD, and we report the results of our investigation of its neuroprotective mechanism in neurons and glial cells. In the murine model, BCP pretreatment ameliorated motor dysfunction, protected against dopaminergic neuronal losses in the SN and striatum, and alleviated MPTP-induced glia activation. Additionally, BCP inhibited the levels of inflammatory cytokines in the nigrostriatal system. The observed neuroprotection and inhibited glia activation were reversed upon treatment with the CB2R selective antagonist AM630, confirming the involvement of the CB2R. These results indicate that BCP acts via multiple neuroprotective mechanisms in our murine model and suggest that BCP may be viewed as a potential treatment and/or preventative agent for PD.
      PubDate: 2017-07-06
      DOI: 10.3390/ph10030060
      Issue No: Vol. 10, No. 3 (2017)
  • Pharmaceuticals, Vol. 10, Pages 61: Pharmaceuticals: Impact Factor or

    • Authors: Jean Vanden Eynde
      First page: 61
      Abstract: n/a
      PubDate: 2017-07-06
      DOI: 10.3390/ph10030061
      Issue No: Vol. 10, No. 3 (2017)
  • Pharmaceuticals, Vol. 10, Pages 62: Synthesis and Antiproliferative
           Activity of Novel Heterocyclic Indole-Trimethoxyphenyl Conjugates

    • Authors: Michael Cahill, Kevin O’Shea, Larry Pierce, Hannah Winfield, Kevin Eccles, Simon Lawrence, Florence McCarthy
      First page: 62
      Abstract: The synthesis and biological evaluation of a series of novel heterocyclic indole derivatives is described. The consolidation of the combretastatin and bisindolylmaleimide templates towards the inclusion of a novel heterocyclic ring proffered a versatile pharmacophore with which to pursue chemical diversification. Given literature precedent, maleimide was initially investigated in this role and the bioactivity assessed by measurement of NCI-60 cell panel growth. Subsequently, a range of 5-aminopyrazoles was designed and developed to explore the specific effect of heterocycle hydrogen bonding on cell growth. The unique electronic nature of the 5-aminopyrazole moiety allowed for regiospecific monosubstitution on different sites of the ring, such as thiourea substitution at the N(1) position for derivative 45 or trifluoroacetylation on the 5-amino position for 43. Further derivatisation led to the ultimate development of bicyclic pyrazolotriazinedione 41 and pyrimidine 42 systems. The antiproliferative activities of these 3,4-diaryl-5-aminopyrazoles were assessed using the NCI-60 cell screen, disclosing the discovery of distinct selectivity profiles towards a number of cell lines, such as SNB-75 CNS cancer, UO-31 and CAKI-1 renal cancer cells. A series of DNA topological assays discounted the interaction with topoisomerase II as a putative mechanism of action.
      PubDate: 2017-07-05
      DOI: 10.3390/ph10030062
      Issue No: Vol. 10, No. 3 (2017)
  • Pharmaceuticals, Vol. 10, Pages 63: Nanofiber Scaffolds as Drug Delivery
           Systems to Bridge Spinal Cord Injury

    • Authors: Angela Faccendini, Barbara Vigani, Silvia Rossi, Giuseppina Sandri, Maria Bonferoni, Carla Caramella, Franca Ferrari
      First page: 63
      Abstract: The complex pathophysiology of spinal cord injury (SCI) may explain the current lack of an effective therapeutic approach for the regeneration of damaged neuronal cells and the recovery of motor functions. A primary mechanical injury in the spinal cord triggers a cascade of secondary events, which are involved in SCI instauration and progression. The aim of the present review is to provide an overview of the therapeutic neuro-protective and neuro-regenerative approaches, which involve the use of nanofibers as local drug delivery systems. Drugs released by nanofibers aim at preventing the cascade of secondary damage (neuro-protection), whereas nanofibrous structures are intended to re-establish neuronal connectivity through axonal sprouting (neuro-regeneration) promotion, in order to achieve a rapid functional recovery of spinal cord.
      PubDate: 2017-07-05
      DOI: 10.3390/ph10030063
      Issue No: Vol. 10, No. 3 (2017)
  • Pharmaceuticals, Vol. 10, Pages 64: Transient Receptor Potential (TRP)
           Channels in Drug Discovery: Old Concepts & New Thoughts

    • Authors: Susan Huang, Arpad Szallasi
      First page: 64
      Abstract: 2017 marks the 20th anniversary of the molecular cloning by David Julius and colleagues (1997) of the long sought-after capsaicin receptor, now known as TRPV1 (Transient Receptor Potential Vanilloid 1) [1]. This seminal discovery has opened up a “hot” new field of basic research and launched drug discovery efforts into the large family (by the latest count 28 mammalian members, 27 in humans) of TRP ion channels [2]. Indeed, it took less than a decade for the first potent, small molecule TRPV1 antagonists to enter phase 1 clinical trials [3]. Yet, despite the large amount of resources that has been invested in TRPV1 research, there are currently no TRPV1-targeted drugs in phase 3 clinical trials. In this special issue of Pharmaceuticals, we aim to capture the progress in the TRP channel field over the past twenty years, with 15 articles covering a variety of TRP channels and potential relevant disease states and applications.
      PubDate: 2017-07-06
      DOI: 10.3390/ph10030064
      Issue No: Vol. 10, No. 3 (2017)
  • Pharmaceuticals, Vol. 10, Pages 65: 5-aza-2′,2′-Difluroro
           Deoxycytidine (NUC013): A Novel Nucleoside DNA Methyl Transferase
           Inhibitor and Ribonucleotide Reductase Inhibitor for the Treatment of

    • Authors: Richard Daifuku, Zhenbo Hu, Yogen Saunthararajah
      First page: 65
      Abstract: Tumor suppressor genes can be silenced genetically as well as epigenetically. One approach to reversing epigenetic suppression of tumor suppressor genes is to inhibit DNA methyl transferase. 5-aza-2′,2′-diflurorodeoxycytidine (NUC013) is a novel DNA methyl transferase and ribonucleotide reductase inhibitor that is a more potent inhibitor of growth than decitabine in the NCI 60 cancer cell line panel. NUC013 is more active than decitabine against p53-null/mutant cancer cell lines (p = 0.027) but is even more so against p53 wild-type (WT) cell lines (p = 0.0025). The maximum tolerated dose in mice of NUC013 is greater than 120 mg/kg administered intravenously for three consecutive days a week for three weeks. With this regimen and a dose of 20 mg/kg in a human leukemia HL-60 (p53-null) NCr-nu/nu mouse xenograft model (n = 10/group), NUC013 demonstrated a survival benefit (saline median survival (MS) = 26.5 days, NUC013 MS = 32 days and hazard ratio (HR) = 0.26 (p = 0.032)). In a colon cancer LoVo (TP53 WT) xenograft, mice treated with decitabine at 5 mg/kg had worse survival than saline controls (decitabine MS = 31 days, saline MS > 60 days and HR = 26.89 (p < 0.0001)). At a dose of 20 mg/kg NUC013, mean tumor volume in the LoVo xenografts was lower than controls by 50.9% and at 40 mg/kg by 53.7% (both p < 0.0001).
      Citation: Pharmaceuticals
      PubDate: 2017-07-20
      DOI: 10.3390/ph10030065
      Issue No: Vol. 10, No. 3 (2017)
  • Pharmaceuticals, Vol. 10, Pages 66: Modernization of Enoxaparin Molecular
           Weight Determination Using Homogeneous Standards

    • Authors: Katelyn Arnold, Stephen Capuzzi, Yongmei Xu, Eugene Muratov, Kevin Carrick, Anita Szajek, Alexander Tropsha, Jian Liu
      First page: 66
      Abstract: Enoxaparin is a low-molecular weight heparin used to treat thrombotic disorders. Following the fatal contamination of the heparin supply chain in 2007–2008, the U.S. Pharmacopeia (USP) and U.S. Food and Drug Administration (FDA) have worked extensively to modernize the unfractionated heparin and enoxaparin monographs. As a result, the determination of molecular weight (MW) has been added to the monograph as a measure to strengthen the quality testing and to increase the protection of the global supply of this life-saving drug. The current USP calibrant materials used for enoxaparin MW determination are composed of a mixture of oligosaccharides; however, they are difficult to reproduce as the calibrants have ill-defined structures due to the heterogeneity of the heparin parent material. To address this issue, we describe a promising approach consisting of a predictive computational model built from a library of chemoenzymatically synthesized heparin oligosaccharides for enoxaparin MW determination. Here, we demonstrate that this test can be performed with greater efficiency by coupling synthetic oligosaccharides with the power of computational modeling. Our approach is expected to improve the MW measurement for enoxaparin.
      Citation: Pharmaceuticals
      PubDate: 2017-07-22
      DOI: 10.3390/ph10030066
      Issue No: Vol. 10, No. 3 (2017)
  • Pharmaceuticals, Vol. 10, Pages 67: Hippocampal Proteome of Rats Subjected
           to the Li-Pilocarpine Epilepsy Model and the Effect of Carisbamate

    • Authors: José Eduardo Marques-Carneiro, Daniele Suzete Persike, Julia Julie Litzahn, Jean-Christophe Cassel, Astrid Nehlig, Maria José da Silva Fernandes
      First page: 67
      Abstract: In adult rats, the administration of lithium–pilocarpine (LiPilo) reproduces most clinical and neuropathological features of human temporal lobe epilepsy (TLE). Carisbamate (CRS) possesses the property of modifying epileptogenesis in this model. Indeed, about 50% of rats subjected to LiPilo status epilepticus (SE) develop non-convulsive seizures (NCS) instead of motor seizures when treated with CRS. However, the mechanisms underlying these effects remain unknown. The aim of this study was to perform a proteomic analysis in the hippocampus of rats receiving LiPilo and developing motor seizures or NCS following CRS treatment. Fifteen adult male Sprague–Dawley rats were used. SE was induced by LiPilo injection. CRS treatment was initiated at 1 h and 9 h after SE onset and maintained for 7 days, twice daily. Four groups were studied after video-EEG control of the occurrence of motor seizures: a control group receiving saline (CT n = 3) and three groups that underwent SE: rats treated with diazepam (DZP n = 4), rats treated with CRS displaying NCS (CRS-NCS n = 4) or motor seizures (CRS-TLE n = 4). Proteomic analysis was conducted by 2D-SDS-PAGE. Twenty-four proteins were found altered. In the CRS-NCS group, proteins related to glycolysis and ATP synthesis were down-regulated while proteins associated with pyruvate catabolism were up-regulated. Moreover, among the other proteins differentially expressed, we found proteins related to inflammatory processes, protein folding, tissue regeneration, response to oxidative stress, gene expression, biogenesis of synaptic vesicles, signal transduction, axonal transport, microtubule formation, cell survival, and neuronal plasticity. Our results suggest a global reduction of glycolysis and cellular energy production that might affect brain excitability. In addition, CRS seems to modulate proteins related to many other pathways that could significantly participate in the epileptogenesis-modifying effect observed.
      Citation: Pharmaceuticals
      PubDate: 2017-07-30
      DOI: 10.3390/ph10030067
      Issue No: Vol. 10, No. 3 (2017)
  • Pharmaceuticals, Vol. 10, Pages 68: Assessment of Bone Metastases in
           Patients with Prostate Cancer—A Comparison between
           99mTc-Bone-Scintigraphy and [68Ga]Ga-PSMA PET/CT

    • Authors: Lena Thomas, Caroline Balmus, Hojjat Ahmadzadehfar, Markus Essler, Holger Strunk, Ralph Bundschuh
      First page: 68
      Abstract: Purpose: Bone scintigraphy is the standard of reference in bone metastases in prostate cancer patients. However, new radiotracers employed in prostate-specific membrane antigen (PSMA)-ligands has led to the growing importance of PET/CT as diagnostic tool. The aim of our study was to investigate the difference between bone scan and PSMA-PET/CT for the detection of bone metastases in prostate cancer. Methods: Thirty patients with bone metastases originating from prostate cancer were examined by 99mTc-MDP bone scan and 68Ga-PSMA-PET/CT within an average of 21 days. Bone scans were analyzed visually according to the number of lesions and using the software package ExiniBONE by Exini Diagnostics. PET/CT data was analyzed visually. Numbers of detected lesions were compared for the different methods for the whole patient and for different regions. In addition, results were compared to serum prostate-specific antigen (PSA), alkaline phosphatase (ALP), bone alkaline phosphatase (bALP), pro gastrin releasing peptide (pGRP) and eastern cooperative oncology group (ECOG) performance status. Results: In the bone scans, visual and semiautomatic lesion detection showed similar results with an average of 19.4 and 17.8 detected bone lesion per patient. However, in PSMA-PET/CT, on average double the numbers of lesions (40.0) were detected. The largest differences were found in the thorax and pelvis, which can be explained by the advantages of tomographic imaging. Bland-Altman analysis showed greater differences in patients with large numbers of bone metastases. Conclusion: No significant difference was found when using semiautomatic analysis compared to visual reading for bone scans. Fewer bone metastases were detected in bone scans than in PSMA-PET/CT. However, in none of our patients would the difference have led to clinical consequences. Therefore, it seems that for patients undergoing PSMA-PET/CT, there is no need to perform additional bone scans if the appropriate PET/CT protocols are applied.
      Citation: Pharmaceuticals
      PubDate: 2017-07-31
      DOI: 10.3390/ph10030068
      Issue No: Vol. 10, No. 3 (2017)
  • Pharmaceuticals, Vol. 10, Pages 69: The Binding Effect of Proteins on
           Medications and Its Impact on Electrochemical Sensing: Antipsychotic
           Clozapine as a Case Study

    • Authors: George Banis, Thomas Winkler, Patricia Barton, Sheryl Chocron, Eunkyoung Kim, Deanna Kelly, Gregory Payne, Hadar Ben-Yoav, Reza Ghodssi
      First page: 69
      Abstract: Clozapine (CLZ), a dibenzodiazepine, is demonstrated as the optimal antipsychotic for patients suffering from treatment-resistant schizophrenia. Like many other drugs, understanding the concentration of CLZ in a patient’s blood is critical for managing the patients’ symptoms, side effects, and overall treatment efficacy. To that end, various electrochemical techniques have been adapted due to their capabilities in concentration-dependent sensing. An open question associated with electrochemical CLZ monitoring is whether drug–protein complexes (i.e., CLZ bound to native blood proteins, such as serum albumin (SA) or alpha-1 acid-glycoprotein (AAG)) contribute to electrochemical redox signals. Here, we investigate CLZ-sensing performance using fundamental electrochemical methods with respect to the impact of protein binding. Specifically, we test the activity of bound and free fractions of a mixture of CLZ and either bovine SA or human AAG. Results suggest that bound complexes do not significantly contribute to the electrochemical signal for mixtures of CLZ with AAG or SA. Moreover, the fraction of CLZ bound to protein is relatively constant at 31% (AAG) and 73% (SA) in isolation with varying concentrations of CLZ. Thus, electrochemical sensing can enable direct monitoring of only the unbound CLZ, previously only accessible via equilibrium dialysis. The methods utilized in this work offer potential as a blueprint in developing electrochemical sensors for application to other redox-active medications with high protein binding more generally. This demonstrates that electrochemical sensing can be a new tool in accessing information not easily available previously, useful toward optimizing treatment regimens.
      Citation: Pharmaceuticals
      PubDate: 2017-08-01
      DOI: 10.3390/ph10030069
      Issue No: Vol. 10, No. 3 (2017)
  • Pharmaceuticals, Vol. 10, Pages 70: Glycosaminoglycan Interactions with
           Chemokines Add Complexity to a Complex System

    • Authors: Amanda Proudfoot, Zoë Johnson, Pauline Bonvin, Tracy Handel
      First page: 70
      Abstract: Chemokines have two types of interactions that function cooperatively to control cell migration. Chemokine receptors on migrating cells integrate signals initiated upon chemokine binding to promote cell movement. Interactions with glycosaminoglycans (GAGs) localize chemokines on and near cell surfaces and the extracellular matrix to provide direction to the cell movement. The matrix of interacting chemokine–receptor partners has been known for some time, precise signaling and trafficking properties of many chemokine–receptor pairs have been characterized, and recent structural information has revealed atomic level detail on chemokine–receptor recognition and activation. However, precise knowledge of the interactions of chemokines with GAGs has lagged far behind such that a single paradigm of GAG presentation on surfaces is generally applied to all chemokines. This review summarizes accumulating evidence which suggests that there is a great deal of diversity and specificity in these interactions, that GAG interactions help fine-tune the function of chemokines, and that GAGs have other roles in chemokine biology beyond localization and surface presentation. This suggests that chemokine–GAG interactions add complexity to the already complex functions of the receptors and ligands.
      Citation: Pharmaceuticals
      PubDate: 2017-08-09
      DOI: 10.3390/ph10030070
      Issue No: Vol. 10, No. 3 (2017)
  • Pharmaceuticals, Vol. 10, Pages 71: Complexes of Oligoribonucleotides with
           D-Mannitol Inhibit Hemagglutinin–Glycan Interaction and Suppress
           Influenza A Virus H1N1 (A/FM/1/47) Infectivity In Vitro

    • Authors: Nataliia Melnichuk, Larisa Semernikova, Zenoviy Tkachuk
      First page: 71
      Abstract: The influenza virus hemagglutinin (HA) mediates both receptor (glycan) binding and membrane fusion for cell entry and has been the basis for subtyping influenza viruses. The oligoribonucleotides-d-mannitol (ORNs-d-M) complexes possess an anti-influenza activity in vitro and in vivo. In the present studies, we have found that ORNs-d-M interferes with hemagglutinin (HA)–glycan interaction and suppress viral infection in host cells. HA–glycan interactions were evaluated to indirectly quantify the amount of influenza virus titer by an agglutination assay. Influenza virus infectivity was determined by TCID50 assay. The direct virucidal action of the complexes was evaluated by both cytopathic effects (CPE) reduction assay and cell MTT assay. We found that ORNs-d-M hinders interaction between HA and glycan. These complexes decreased the infectivity of influenza virus and had a direct virucidal action. ORNs-d-M reduces influenza virus infectivity, affecting the HA–glycan interaction in vitro. By suppressing the influenza viral infection, the ORNs-d-M can have direct virucidal action.
      Citation: Pharmaceuticals
      PubDate: 2017-08-09
      DOI: 10.3390/ph10030071
      Issue No: Vol. 10, No. 3 (2017)
  • Pharmaceuticals, Vol. 10, Pages 72: Folate Receptor-Positive Gynecological
           Cancer Cells: In Vitro and In Vivo Characterization

    • Authors: Klaudia Siwowska, Raffaella Schmid, Susan Cohrs, Roger Schibli, Cristina Müller
      First page: 72
      Abstract: The folate receptor (FR) is expressed in a variety of gynecological cancer types. It has been widely used for tumor targeting with folic acid conjugates of diagnostic and therapeutic probes. The cervical KB tumor cells have evolved as the standard model for preclinical investigations of folate-based (radio) conjugates. In this study, a panel of FR-expressing human cancer cell lines—including cervical (HeLa, KB, KB-V1), ovarian (IGROV-1, SKOV-3, SKOV-3.ip), choriocarcinoma (JAR, BeWo) and endometrial (EFE-184) tumor cells—was investigated in vitro and for their ability to grow as xenografts in mice. FR-expression levels were compared in vitro and in vivo and the cell lines were characterized by determination of the sensitivity towards commonly-used chemotherapeutics and the expression of two additional, relevant tumor markers, HER2 and L1-CAM. It was found that, besides KB cells, its multiresistant KB-V1 subclone as well as the ovarian cancer cell lines, IGROV-1 and SKOV-3.ip, could be used as potentially more relevant preclinical models. They would allow addressing specific questions such as the therapeutic efficacy of FR-targeting agents in tumor (mouse) models of multi-resistance and in mouse models of metastases formation.
      Citation: Pharmaceuticals
      PubDate: 2017-08-15
      DOI: 10.3390/ph10030072
      Issue No: Vol. 10, No. 3 (2017)
  • Pharmaceuticals, Vol. 10, Pages 73: Role of CYP2C9, CYP2C19 and EPHX
           Polymorphism in the Pharmacokinetic of Phenytoin: A Study on Uruguayan
           Caucasian Subjects

    • Authors: Natalia Guevara, Cecilia Maldonado, Manuel Uría, Raquel González, Manuel Ibarra, Silvana Alvariza, Antonella Carozzi, Carlos Azambuja, Pietro Fagiolino, Marta Vázquez
      First page: 73
      Abstract: Phenytoin (PHT) oxidative route leads to its main metabolite p-hydroxyphenytoin (p-HPPH), by means of CYP2C9 and CYP2C19. Formation of p-HPPH proceeds via a reactive arene-oxide intermediate. This intermediate can also be converted into PHT dihydrodiol by microsomal epoxide hydrolase (EPHX). The three enzymes are polymorphically expressed and the genetic variants are responsible for changes in the enzyme activity. In order to evaluate the effect that these polymorphisms have on PHT metabolism, PHT and p-HPPH plasma concentrations were measured and the genotype for the three enzymes was assessed in 50 Uruguayan epileptic patients. 30% of the patients were intermediate and 2% were poor metabolizers for CYP2C9, while 20% were intermediate metabolizers for CYP2C19. 44%, 10%, and 46% of subjects had intermediate, increased and decreased activities of EPHX respectively. CYP2C9 was confirmed to be the main responsible enzyme for PHT biotransformation. CYP2C19 seemed to be preponderant in p-HPPH oxidative metabolism. Apart from being responsible for the production of the dihydrodiol metabolite, EPHX also seemed to contribute to pHPPH formation when its activity is low. PHT might be recovered with a decreased activity of EPHX regardless the activity of CYP2C9.
      Citation: Pharmaceuticals
      PubDate: 2017-08-18
      DOI: 10.3390/ph10030073
      Issue No: Vol. 10, No. 3 (2017)
  • Pharmaceuticals, Vol. 10, Pages 74: Synthesis of Nitric Oxide Donors
           Derived from Piloty’s Acid and Study of Their Effects on Dopamine
           Secretion from PC12 Cells

    • Authors: Daniele Sanna, Gaia Rocchitta, Maria Serra, Marcello Abbondio, Pier Serra, Rossana Migheli, Lidia De Luca, Eugenio Garribba, Andrea Porcheddu
      First page: 74
      Abstract: This study investigated the mechanisms and kinetics of nitric oxide (NO) generation by derivatives of Piloty’s acid (NO-donors) under physiological conditions. In order to qualitatively and quantitatively measure NO release, electron paramagnetic resonance (EPR) was carried out with NO spin trapping. In addition, voltammetric techniques, including cyclic voltammetry and constant potential amperometry, were used to confirm NO release from Piloty’s acid and its derivatives. The resulting data showed that Piloty’s acid derivatives are able to release NO under physiological conditions. In particular, electron-withdrawing substituents favoured NO generation, while electron-donor groups reduced NO generation. In vitro microdialysis, performed on PC12 cell cultures, was used to evaluate the dynamical secretion of dopamine induced by the Piloty’s acid derivatives. Although all the studied molecules were able to induce DA secretion from PC12, only those with a slow release of NO have not determined an autoxidation of DA itself. These results confirm that the time-course of NO-donors decomposition and the amount of NO released play a key role in dopamine secretion and auto-oxidation. This information could drive the synthesis or the selection of compounds to use as potential drugs for the therapy of Parkinson’s disease (PD).
      Citation: Pharmaceuticals
      PubDate: 2017-09-05
      DOI: 10.3390/ph10030074
      Issue No: Vol. 10, No. 3 (2017)
  • Pharmaceuticals, Vol. 10, Pages 75: Behavioral and Neurochemical
           Consequences of Pentylenetetrazol-Induced Kindling in Young and
           Middle-Aged Rats

    • Authors: Alexandre Hoeller, Cristiane de Carvalho, Pedro Franco, Douglas Formolo, Alexandre Imthon, Henrique dos Santos, Ingrid Eidt, Gabriel Souza, Leandra Constantino, Camila Ferreira, Rui Prediger, Rodrigo Bainy Leal, Roger Walz
      First page: 75
      Abstract: (1) Objectives: Epilepsy disorder is likely to increase with aging, leading to an increased incidence of comorbidities and mortality. In spite of that, there is a lack of information regarding this issue and little knowledge of cognitive and emotional responses in aging subjects following epileptogenesis. We investigated whether and how aging distress epilepsy-related behavioral and biochemical outcomes are associated with cognition and emotion. (2) Methods: Young and middle-aged Wistar rats (3 or 12 months old) were treated with pentylenetetrazol (PTZ, 35 mg/kg) and injected on alternated days for 20 (young rats) and 32 days (middle-aged rats). Kindling was reached after two consecutive stages 4 plus one stage 5 or 6 in Racine scale. Control and kindled rats were evaluated in the elevated plus-maze (EPM) and object-recognition tests and their hippocampus was collected 24 h later for mitogen-activated protein kinases (MAPK) dosage. (3) Results: Middle-aged rats presented a higher resistance to develop kindling, with a decrease in the seizure severity index observed following the 4th and 9th PTZ injections. Middle-aged rats displayed an increased duration of the first myoclonic seizure and an increased latency to the first generalized seizure when compared to younger rats. The induction of kindling did not impair the animals’ performance (regardless of age) in the object-recognition task and the EPM test as well as it did not alter the hippocampal levels of MAPKs. (4) Significance: Our findings reveal that, despite age-related differences during epileptogenesis, middle-aged rats evaluated after kindling performed similarly during discriminative learning and emotional tasks in comparison to young animals, with no alteration of hippocampal MAPKs. Additional investigation must be carried out to explore the electrophysiological mechanisms underlying these responses, as well as the long-term effects displayed after kindling.
      Citation: Pharmaceuticals
      PubDate: 2017-09-13
      DOI: 10.3390/ph10030075
      Issue No: Vol. 10, No. 3 (2017)
  • Pharmaceuticals, Vol. 10, Pages 76: Comparison of In Vitro Assays in
           Selecting Radiotracers for In Vivo P-Glycoprotein PET Imaging

    • Authors: Renske Raaphorst, Heli Savolainen, Mariangela Cantore, Evita van de Steeg, Aren van Waarde, Nicola Colabufo, Philip Elsinga, Adriaan Lammertsma, Albert Windhorst, Gert Luurtsema
      First page: 76
      Abstract: Positron emission tomography (PET) imaging of P-glycoprotein (P-gp) in the blood-brain barrier can be important in neurological diseases where P-gp is affected, such as Alzheimer´s disease. Radiotracers used in the imaging studies are present at very small, nanomolar, concentration, whereas in vitro assays where these tracers are characterized, are usually performed at micromolar concentration, causing often discrepant in vivo and in vitro data. We had in vivo rodent PET data of [11C]verapamil, (R)-N-[18F]fluoroethylverapamil, (R)-O-[18F]fluoroethyl-norverapamil, [18F]MC225 and [18F]MC224 and we included also two new molecules [18F]MC198 and [18F]KE64 in this study. To improve the predictive value of in vitro assays, we labeled all the tracers with tritium and performed bidirectional substrate transport assay in MDCKII-MDR1 cells at three different concentrations (0.01, 1 and 50 µM) and also inhibition assay with P-gp inhibitors. As a comparison, we used non-radioactive molecules in transport assay in Caco-2 cells at a concentration of 10 µM and in calcein-AM inhibition assay in MDCKII-MDR1 cells. All the P-gp substrates were transported dose-dependently. At the highest concentration (50 µM), P-gp was saturated in a similar way as after treatment with P-gp inhibitors. Best in vivo correlation was obtained with the bidirectional transport assay at a concentration of 0.01 µM. One micromolar concentration in a transport assay or calcein-AM assay alone is not sufficient for correct in vivo prediction of substrate P-gp PET ligands.
      Citation: Pharmaceuticals
      PubDate: 2017-09-20
      DOI: 10.3390/ph10030076
      Issue No: Vol. 10, No. 3 (2017)
  • Pharmaceuticals, Vol. 10, Pages 33: An Updated View on an Emerging Target:
           Selected Papers from the 8th International Conference on Protein Kinase

    • Authors: Joachim Jose, Marc Le-Borgne, Lorenzo Pinna, Mathias Montenarh
      First page: 33
      Abstract: n/a
      PubDate: 2017-03-23
      DOI: 10.3390/ph10020033
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 34: Pathophysiological Significance of
           Dermatan Sulfate Proteoglycans Revealed by Human Genetic Disorders

    • Authors: Shuji Mizumoto, Tomoki Kosho, Shuhei Yamada, Kazuyuki Sugahara
      First page: 34
      Abstract: The indispensable roles of dermatan sulfate-proteoglycans (DS-PGs) have been demonstrated in various biological events including construction of the extracellular matrix and cell signaling through interactions with collagen and transforming growth factor-β, respectively. Defects in the core proteins of DS-PGs such as decorin and biglycan cause congenital stromal dystrophy of the cornea, spondyloepimetaphyseal dysplasia, and Meester-Loeys syndrome. Furthermore, mutations in human genes encoding the glycosyltransferases, epimerases, and sulfotransferases responsible for the biosynthesis of DS chains cause connective tissue disorders including Ehlers-Danlos syndrome and spondyloepimetaphyseal dysplasia with joint laxity characterized by skin hyperextensibility, joint hypermobility, and tissue fragility, and by severe skeletal disorders such as kyphoscoliosis, short trunk, dislocation, and joint laxity. Glycobiological approaches revealed that mutations in DS-biosynthetic enzymes cause reductions in enzymatic activities and in the amount of synthesized DS and also disrupt the formation of collagen bundles. This review focused on the growing number of glycobiological studies on recently reported genetic diseases caused by defects in the biosynthesis of DS and DS-PGs.
      PubDate: 2017-03-27
      DOI: 10.3390/ph10020034
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 35: Modulation of TRP Channel Activity by
           Hydroxylation and Its Therapeutic Potential

    • Authors: Yagnesh Nagarajan, Grigori Y. Rychkov, Daniel J. Peet
      First page: 35
      Abstract: Two transient receptor potential (TRP) channels—TRPA1 and TRPV3—are post-translationally hydroxylated, resulting in oxygen-dependent regulation of channel activity. The enzymes responsible are the HIF prolyl hydroxylases (PHDs) and the asparaginyl hydroxylase factor inhibiting HIF (FIH). The PHDs and FIH are well characterized for their hydroxylation of the hypoxic inducible transcription factors (HIFs), mediating their hypoxic regulation. Consequently, these hydroxylases are currently being targeted therapeutically to modulate HIF activity in anemia, inflammation, and ischemic disease. Modulating the HIFs by targeting these hydroxylases may result in both desirable and undesirable effects on TRP channel activity, depending on the physiological context. For the best outcomes, these hydroxylases could be therapeutically targeted in pathologies where activation of both the HIFs and the relevant TRP channels are predicted to independently achieve positive outcomes, such as wound healing and obesity.
      PubDate: 2017-03-27
      DOI: 10.3390/ph10020035
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 36: Development of a Glycosaminoglycan
           Derived, Selectin Targeting Anti-Adhesive Coating to Treat Endothelial
           Cell Dysfunction

    • Authors: James Wodicka, Andrea Chambers, Gurneet Sangha, Craig Goergen, Alyssa Panitch
      First page: 36
      Abstract: Endothelial cell (EC) dysfunction is associated with many disease states including deep vein thrombosis (DVT), chronic kidney disease, sepsis and diabetes. Loss of the glycocalyx, a thin glycosaminoglycan (GAG)-rich layer on the EC surface, is a key feature of endothelial dysfunction and increases exposure of EC adhesion molecules such as selectins, which are involved in platelet binding to ECs. Once bound, platelets cause thrombus formation and an increased inflammatory response. We have developed a GAG derived, selectin targeting anti-adhesive coating (termed EC-SEAL) consisting of a dermatan sulfate backbone and multiple selectin-binding peptides designed to bind to inflamed endothelium and prevent platelet binding to create a more quiescent endothelial state. Multiple EC-SEAL variants were evaluated and the lead variant was found to preferentially bind to selectin-expressing ECs and smooth muscle cells (SMCs) and inhibit platelet binding and activation in a dose-dependent manner. In an in vivo model of DVT, treatment with the lead variant resulted in reduced thrombus formation. These results indicate that EC-SEAL has promise as a potential therapeutic in the treatment of endothelial dysfunction.
      PubDate: 2017-03-29
      DOI: 10.3390/ph10020036
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 37: Development of TRPM8 Antagonists to
           Treat Chronic Pain and Migraine

    • Authors: Andy Weyer, Sonya Lehto
      First page: 37
      Abstract: A review. Development of pharmaceutical antagonists of transient receptor potential melastatin 8 (TRPM8) have been pursued for the treatment of chronic pain and migraine. This review focuses on the current state of this progress.
      PubDate: 2017-03-30
      DOI: 10.3390/ph10020037
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 38: Systematic Analysis of Pharmaceutical
           Preparations of Chondroitin Sulfate Combined with Glucosamine

    • Authors: Gustavo Santos, Adriana Piquet, Bianca Glauser, Ana Tovar, Mariana Pereira, Eduardo Vilanova, Paulo Mourão
      First page: 38
      Abstract: Glycosaminoglycans are carbohydrate-based compounds widely employed as nutraceuticals or prescribed drugs. Oral formulations of chondroitin sulfate combined with glucosamine sulfate have been increasingly used to treat the symptoms of osteoarthritis and osteoarthrosis. The chondroitin sulfate of these combinations can be obtained from shark or bovine cartilages and hence presents differences regarding the proportions of 4- and 6-sulfated N-acetyl β-d-galactosamine units. Herein, we proposed a systematic protocol to assess pharmaceutical batches of this combination drug. Chemical analyses on the amounts of chondroitin sulfate and glucosamine in the batches were in accordance with those declared by the manufacturers. Anion-exchange chromatography has proven more effective than electrophoresis to determine the type of chondroitin sulfate present in the combinations and to detect the presence of keratan sulfate, a common contaminant found in batches prepared with shark chondroitin sulfate. 1D NMR spectra revealed the presence of non-sulfated instead of sulfated glucosamine in the formulations and thus in disagreement with the claims declared on the label. Moreover, 1D and 2D NMR analyses allowed a precise determination on the chemical structures of the chondroitin sulfate present in the formulations. The set of analytical tools suggested here could be useful as guidelines to improve the quality of this medication.
      PubDate: 2017-04-01
      DOI: 10.3390/ph10020038
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 39: Role of TRPM7 in Cancer: Potential as
           Molecular Biomarker and Therapeutic Target

    • Authors: Nelson Yee
      First page: 39
      Abstract: The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a ubiquitously expressed ion channel with intrinsic kinase activity. Molecular and electrophysiological analyses of the structure and activity of TRPM7 have revealed functional coupling of its channel and kinase activity. Studies have indicated the important roles of TRPM7 channel-kinase in fundamental cellular processes, physiological responses, and embryonic development. Accumulating evidence has shown that TRPM7 is aberrantly expressed and/or activated in human diseases including cancer. TRPM7 plays a variety of functional roles in cancer cells including survival, cell cycle progression, proliferation, growth, migration, invasion, and epithelial-mesenchymal transition (EMT). Data from a study using mouse xenograft of human cancer show that TRPM7 is required for tumor growth and metastasis. The aberrant expression of TRPM7 and its genetic mutations/polymorphisms have been identified in various types of carcinoma. Chemical modulators of TRPM7 channel produced inhibition of proliferation, growth, migration, invasion, invadosome formation, and markers of EMT in cancer cells. Taken together, these studies suggest the potential value of exploiting TRPM7 channel-kinase as a molecular biomarker and therapeutic target in human malignancies.
      PubDate: 2017-04-05
      DOI: 10.3390/ph10020039
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 40: Novel Proteasome Inhibitors and
           Histone Deacetylase Inhibitors: Progress in Myeloma Therapeutics

    • Authors: Saurabh Chhabra
      First page: 40
      Abstract: The unfolded protein response is responsible for the detection of misfolded proteins and the coordination of their disposal and is necessary to maintain the cellular homoeostasis. Multiple myeloma cells secrete large amounts of immunoglobulins, proteins that need to be correctly folded by the chaperone system. If this process fails, the misfolded proteins have to be eliminated by the two main garbage-disposal systems of the cell: proteasome and aggresome. The blockade of either of these systems will result in accumulation of immunoglobulins and other toxic proteins in the cytoplasm and cell death. The simultaneous inhibition of the proteasome, by proteasome inhibitors (PIs) and the aggresome, by histone deacetylase inhibitors (HDACi) results in a synergistic increase in cytotoxicity in myeloma cell lines. This review provides an overview of mechanisms of action of second-generation PIs and HDACi in multiple myeloma (MM), the clinical results currently observed with these agents and assesses the potential therapeutic impact of the different agents in the two classes. The second-generation PIs offer benefits in terms of increased efficacy, reduced neurotoxicity as off-target effect and may overcome resistance to bortezomib because of their different chemical structure, mechanism of action and biological properties. HDACi with anti-myeloma activity in clinical development discussed in this review include vorinostat, panobinostat and selective HDAC6 inhibitor, ricolinostat.
      PubDate: 2017-04-11
      DOI: 10.3390/ph10020040
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 41: Biotinylated Chlorin and Its Zinc and
           Indium Complexes: Synthesis and In Vitro Biological Evaluation for
           Photodynamic Therapy

    • Authors: Meden Isaac-Lam, Dewana Hammonds
      First page: 41
      Abstract: The synthesis and characterization of biotinylated chlorin photosensitizer and the corresponding zinc and indium complexes are described for potential applications in photodynamic therapy (PDT) for cancer. Phototoxicity of the biotin-chlorin conjugate and the metallated complexes was determined in colon carcinoma CT26 cell lines known to overexpress biotin (Vit B7) receptors. Cell survival assay indicated that the biotinylated chlorin and indium complex showed increased cell growth inhibition than the zinc complex and the starting chlorin (methyl pheophorbide). Fluorescence microcopy studies revealed the generation of apoptotic cells upon light irradiation of colon cells treated with the indium complex. Targeting biotin receptors in cancer cells can improve specificity of photosensitizers for PDT applications.
      PubDate: 2017-04-15
      DOI: 10.3390/ph10020041
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 42: Glycosaminoglycan Binding and
           Non-Endocytic Membrane Translocation of Cell-Permeable Octaarginine
           Monitored by Real-Time In-Cell NMR Spectroscopy

    • Authors: Yuki Takechi-Haraya, Kenzo Aki, Yumi Tohyama, Yuichi Harano, Toru Kawakami, Hiroyuki Saito, Emiko Okamura
      First page: 42
      Abstract: Glycosaminoglycans (GAGs), which are covalently-linked membrane proteins at the cell surface have recently been suggested to involve in not only endocytic cellular uptake but also non-endocytic direct cell membrane translocation of arginine-rich cell-penetrating peptides (CPPs). However, in-situ comprehensive observation and the quantitative analysis of the direct membrane translocation processes are challenging, and the mechanism therefore remains still unresolved. In this work, real-time in-cell NMR spectroscopy was applied to investigate the direct membrane translocation of octaarginine (R8) into living cells. By introducing 4-trifluoromethyl-l-phenylalanine to the N terminus of R8, the non-endocytic membrane translocation of 19F-labeled R8 (19F-R8) into a human myeloid leukemia cell line was observed at 4 °C with a time resolution in the order of minutes. 19F NMR successfully detected real-time R8 translocation: the binding to anionic GAGs at the cell surface, followed by the penetration into the cell membrane, and the entry into cytosol across the membrane. The NMR concentration analysis enabled quantification of how much of R8 was staying in the respective translocation processes with time in situ. Taken together, our in-cell NMR results provide the physicochemical rationale for spontaneous penetration of CPPs in cell membranes.
      PubDate: 2017-04-15
      DOI: 10.3390/ph10020042
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 43: Information Phage Therapy Research
           Should Report

    • Authors: Stephen T. Abedon
      First page: 43
      Abstract: Bacteriophages, or phages, are viruses which infect bacteria. A large subset of phages infect bactericidally and, consequently, for nearly one hundred years have been employed as antibacterial agents both within and outside of medicine. Clinically these applications are described as phage or bacteriophage therapy. Alternatively, and especially in the treatment of environments, this practice instead may be described as a phage-mediated biocontrol of bacteria. Though the history of phage therapy has involved substantial clinical experimentation, current standards along with drug regulations have placed a premium on preclinical approaches, i.e., animal experiments. As such, it is important for preclinical experiments not only to be held to high standards but also to be reported in a manner which improves translation to clinical utility. Here I address this latter issue, that of optimization of reporting of preclinical as well as clinical experiments. I do this by providing a list of pertinent information and data which, in my opinion, phage therapy experiments ought to present in publications, along with tips for best practices. The goal is to improve the ability of readers to gain relevant information from reports on phage therapy research, to allow other researchers greater potential to repeat or extend findings, to ease transitions from preclinical to clinical development, and otherwise simply to improve phage therapy experiments. Targeted are not just authors but also reviewers, other critical readers, writers of commentaries, and, perhaps, formulators of guidelines or policy. Though emphasizing therapy, many points are applicable to phage-mediated biocontrol of bacteria more generally.
      PubDate: 2017-04-30
      DOI: 10.3390/ph10020043
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 44: Pathogenesis and Inhibition of
           Flaviviruses from a Carbohydrate Perspective

    • Authors: So Kim, Bing Li, Robert Linhardt
      First page: 44
      Abstract: Flaviviruses are enveloped, positive single stranded ribonucleic acid (RNA) viruses with various routes of transmission. While the type and severity of symptoms caused by pathogenic flaviviruses vary from hemorrhagic fever to fetal abnormalities, their general mechanism of host cell entry is similar. All pathogenic flaviviruses, such as dengue virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, and Zika virus, bind to glycosaminglycans (GAGs) through the putative GAG binding sites within their envelope proteins to gain access to the surface of host cells. GAGs are long, linear, anionic polysaccharides with a repeating disaccharide unit and are involved in many biological processes, such as cellular signaling, cell adhesion, and pathogenesis. Flavivirus envelope proteins are N-glycosylated surface proteins, which interact with C-type lectins, dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) through their glycans. In this review, we discuss both host and viral surface receptors that have the carbohydrate components, focusing on the surface interactions in the early stage of flavivirus entry. GAG-flavivirus envelope protein interactions as well as interactions between flavivirus envelope proteins and DC-SIGN are discussed in detail. This review also examines natural and synthetic inhibitors of flaviviruses that are carbohydrate-based or carbohydrate-targeting. Both advantages and drawbacks of these inhibitors are explored, as are potential strategies to improve their efficacy to ultimately help eradicate flavivirus infections.
      PubDate: 2017-05-04
      DOI: 10.3390/ph10020044
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 45: Novel Radiolabeled Bisphosphonates for
           PET Diagnosis and Endoradiotherapy of Bone Metastases

    • Authors: Nina Pfannkuchen, Marian Meckel, Ralf Bergmann, Michael Bachmann, Chandrasekhar Bal, Mike Sathekge, Wolfgang Mohnike, Richard Baum, Frank Rösch
      First page: 45
      Abstract: Bone metastases, often a consequence of breast, prostate, and lung carcinomas, are characterized by an increased bone turnover, which can be visualized by positron emission tomography (PET), as well as single-photon emission computed tomography (SPECT). Bisphosphonate complexes of 99mTc are predominantly used as SPECT tracers. In contrast to SPECT, PET offers a higher spatial resolution and, owing to the 68Ge/68Ga generator, an analog to the established 99mTc generator exists. Complexation of Ga(III) requires the use of chelators. Therefore, DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), NOTA (1,4,7-triazacyclododecane-1,4,7-triacetic acid), and their derivatives, are often used. The combination of these macrocyclic chelators and bisphosphonates is currently studied worldwide. The use of DOTA offers the possibility of a therapeutic application by complexing the β-emitter 177Lu. This overview describes the possibility of diagnosing bone metastases using [68Ga]Ga-BPAMD (68Ga-labeled (4-{[bis-(phosphonomethyl))carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid) as well as the successful application of [177Lu]Lu-BPAMD for therapy and the development of new diagnostic and therapeutic tools based on this structure. Improvements concerning both the chelator and the bisphosphonate structure are illustrated providing new 68Ga- and 177Lu-labeled bisphosphonates offering improved pharmacological properties.
      PubDate: 2017-05-18
      DOI: 10.3390/ph10020045
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 46: PKC in Regenerative Therapy: New
           Insights for Old Targets

    • Authors: Marta Rui, Rita Nasti, Emanuele Bignardi, Serena Della Volpe, Giacomo Rossino, Daniela Rossi, Simona Collina
      First page: 46
      Abstract: Effective therapies for chronic or non-healing wounds are still lacking. These tissue insults often result in severe clinical complications (i.e., infections and/or amputation) and sometimes lead to patient death. Accordingly, several research groups have focused their efforts in finding innovative and powerful therapeutic strategies to overcome these issues. On the basis of these considerations, the comprehension of the molecular cascades behind these pathological conditions could allow the identification of molecules against chronic wounds. In this context, the regulation of the Protein Kinase C (PKC) cascade has gained relevance in the prevention and/or reparation of tissue damages. This class of phosphorylating enzymes has already been considered for different physiological and pathological pathways and modulation of such enzymes may be useful in reparative processes. Herein, the recent developments in this field will be disclosed, highlighting the pivotal role of PKC α and δ in regenerative medicine. Moreover, an overview of well-established PKC ligands, acting via the modulation of these isoenzymes, will be deeply investigated. This study is aimed at re-evaluating widely known PKC modulators, currently utilized for treating other diseases, as fruitful molecules in wound-healing.
      PubDate: 2017-05-18
      DOI: 10.3390/ph10020046
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 47: Synthesis and Pharmacological
           Properties of Novel Esters Based on Monoterpenoids and Glycine

    • Authors: Mariia Nesterkina, Iryna Kravchenko
      First page: 47
      Abstract: Esters based on mono- and bicyclic terpenoids with glycine have been synthesized via Steglich esterification and characterized by 1H-NMR, IR, and mass spectral studies. Their analgesic and anti-inflammatory activities were investigated after transdermal delivery on models of formalin, capsaicin, and AITC-induced pain, respectively. Glycine esters of menthol and borneol exhibited higher antinociceptive action, whereas eugenol derivative significantly suppressed the development of the inflammatory process. The mechanism of competitive binding between terpenoid esters and TRPA1/TRPV1 agonists was proposed explaining significant analgesic effect of synthesized derivatives. For an explanation of high anti-inflammatory activity, competitive inhibition between terpenoid esters and AITC for binding sites of the TRPA1 ion channel has been suggested.
      PubDate: 2017-05-18
      DOI: 10.3390/ph10020047
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 48: Announcing the 2017 Pharmaceuticals
           Travel Award for Young Post-Doctoral Researchers

    • Authors: Jean Vanden Eynde
      First page: 48
      Abstract: Last year, for the first time in its history, our Journal was able to offer a travel grant of 800 CHF to a young researcher in the field of medicinal chemistry
      PubDate: 2017-05-22
      DOI: 10.3390/ph10020048
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 49: Syntheses of Radioiodinated
           Pyrimidine-2,4,6-Triones as Potential Agents for Non-Invasive Imaging of
           Matrix Metalloproteinases

    • Authors: Hans-Jörg Breyholz, Klaus Kopka, Michael Schäfers, Stefan Wagner
      First page: 49
      Abstract: Dysregulated expression or activation of matrix metalloproteinases (MMPs) is observed in many kinds of live-threatening diseases. Therefore, MMP imaging for example with radiolabelled MMP inhibitors (MMPIs) potentially represents a valuable tool for clinical diagnostics using non-invasive single photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging. This work includes the organic chemical syntheses and in vitro evaluation of five iodinated barbiturate based MMPIs and the selection of derivative 9 for radiosyntheses of isotopologues [123I]9 potentially useful for MMP SPECT imaging and [124I]9 for MMP PET imaging.
      PubDate: 2017-05-30
      DOI: 10.3390/ph10020049
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 50: Chiral Derivatives of Xanthones:
           Investigation of the Effect of Enantioselectivity on Inhibition of
           Cyclooxygenases (COX-1 and COX-2) and Binding Interaction with Human Serum

    • Authors: Carla Fernandes, Andreia Palmeira, Inês Ramos, Carlos Carneiro, Carlos Afonso, Maria Tiritan, Honorina Cidade, Paula Pinto, M. Saraiva, Salette Reis, Madalena Pinto
      First page: 50
      Abstract: Searching of new enantiomerically pure chiral derivatives of xanthones (CDXs) with potential pharmacological properties, particularly those with anti-inflammatory activity, has remained an area of interest of our group. Herein, we describe in silico studies and in vitro inhibitory assays of cyclooxygenases (COX-1 and COX-2) for different enantiomeric pairs of CDXs. The evaluation of the inhibitory activities was performed by using the COX Inhibitor Screening Assay Kit. Docking simulations between the small molecules (CDXs; known ligands and decoys) and the enzyme targets were undertaken with AutoDock Vina embedded in PyRx—Virtual Screening Tool software. All the CDXs evaluated exhibited COX-1 and COX-2 inhibition potential as predicted. Considering that the (S)-(−)-enantiomer of the nonsteroidal anti-inflammatory drug ketoprofen preferentially binds to albumin, resulting in lower free plasma concentration than (R)-(+)-enantiomer, protein binding affinity for CDXs was also evaluated by spectrofluorimetry as well as in in silico. For some CDXs enantioselectivity was observed.
      PubDate: 2017-05-31
      DOI: 10.3390/ph10020050
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 51: Advances in Drug Discovery of New
           Antitubercular Multidrug-Resistant Compounds

    • Authors: Guilherme Fernandes, Chung Man Chin, Jean Dos Santos
      First page: 51
      Abstract: Tuberculosis (TB), a disease caused mainly by the Mycobacterium tuberculosis (Mtb), is according to the World Health Organization (WHO) the infectious disease responsible for the highest number of deaths worldwide. The increased number of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains, and the ineffectiveness of the current treatment against latent tuberculosis are challenges to be overcome in the coming years. The scenario of drug discovery becomes alarming when it is considered that the number of new drugs does not increase proportionally to the emergence of drug resistance. In this review, we will demonstrate the current advances in antitubercular drug discovery, focusing on the research of compounds with potent antituberculosis activity against MDR-TB strains. Herein, active compounds against MDR-TB with minimum inhibitory concentrations (MICs) less than 11 µM and low toxicity published in the last 4 years in the databases PubMed, Web of Science and Scopus will be presented and discussed.
      PubDate: 2017-06-01
      DOI: 10.3390/ph10020051
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 52: Anti-Mycobacterial Evaluation of
           7-Chloro-4-Aminoquinolines and Hologram Quantitative Structure–Activity
           Relationship (HQSAR) Modeling of Amino–Imino Tautomers

    • Authors: Marcelle Bispo, Camilo Lima, Laura Cardoso, André Candéa, Flávio Bezerra, Maria Lourenço, Maria Henriques, Ricardo Alencastro, Carlos Kaiser, Marcus Souza, Magaly Albuquerque
      First page: 52
      Abstract: In an ongoing research program for the development of new anti-tuberculosis drugs, we synthesized three series (A, B, and C) of 7-chloro-4-aminoquinolines, which were evaluated in vitro against Mycobacterium tuberculosis (MTB). Now, we report the anti-MTB and cytotoxicity evaluations of a new series, D (D01–D21). Considering the active compounds of series A (A01–A13), B (B01–B13), C (C01–C07), and D (D01–D09), we compose a data set of 42 compounds and carried out hologram quantitative structure–activity relationship (HQSAR) analysis. The amino–imino tautomerism of the 4-aminoquinoline moiety was considered using both amino (I) and imino (II) forms as independent datasets. The best HQSAR model from each dataset was internally validated and both models showed significant statistical indexes. Tautomer I model: leave-one-out (LOO) cross-validated correlation coefficient (q2) = 0.80, squared correlation coefficient (r2) = 0.97, standard error (SE) = 0.12, cross-validated standard error (SEcv) = 0.32. Tautomer II model: q2 = 0.77, r2 = 0.98, SE = 0.10, SEcv = 0.35. Both models were externally validated by predicting the activity values of the corresponding test set, and the tautomer II model, which showed the best external prediction performance, was used to predict the biological activity responses of the compounds that were not evaluated in the anti-MTB trials due to poor solubility, pointing out D21 for further solubility studies to attempt to determine its actual biological activity.
      PubDate: 2017-06-09
      DOI: 10.3390/ph10020052
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 53: In Vitro and In Vivo Studies of
           Alar-Nasal Cartilage Using Autologous Micro-Grafts: The Use of the
           Rigenera® Protocol in the Treatment of an Osteochondral Lesion of the

    • Authors: Gabriele Ceccarelli, Pietro Gentile, Marco Marcarelli, Martina Balli, Flavio Ronzoni, Laura Benedetti, Maria Cusella De Angelis
      First page: 53
      Abstract: Cartilage defects represent a serious problem due to the poor regenerative properties of this tissue. Regarding the nose, nasal valve collapse is associated with nasal blockage and persistent airway obstruction associated with a significant drop in the quality of life for patients. In addition to surgical techniques, several cell-based tissue-engineering strategies are studied to improve cartilage support in the nasal wall, that is, to ameliorate wall insufficiency. Nevertheless, there are no congruent data available on the benefit for patients during the follow-up time. In this manuscript, we propose an innovative approach in the treatment of cartilage defects in the nose (nasal valve collapse) based on autologous micro-grafts obtained by mechanical disaggregation of a small portion of cartilage tissue (Rigenera® protocol). In particular, we first analyzed in vitro murine and human cartilage micro-grafts; secondly, we analyzed the clinical results of a patient with pinched nose deformity treated with autologous micro-grafts of chondrocytes obtained by Rigenera® protocol. The use of autologous micro-graft produced promising results in surgery treatment of cartilage injuries and could be safely and easily administrated to patients with cartilage tissue defects.
      PubDate: 2017-06-13
      DOI: 10.3390/ph10020053
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 54: The Good the Bad and the Ugly of
           Glycosaminoglycans in Tissue Engineering Applications

    • Authors: Bethanie I. Ayerst, Catherine L.R. Merry, Anthony J. Day
      First page: 54
      Abstract: High sulfation, low cost, and the status of heparin as an already FDA- and EMA- approved product, mean that its inclusion in tissue engineering (TE) strategies is becoming increasingly popular. However, the use of heparin may represent a naïve approach. This is because tissue formation is a highly orchestrated process, involving the temporal expression of numerous growth factors and complex signaling networks. While heparin may enhance the retention and activity of certain growth factors under particular conditions, its binding ‘promiscuity’ means that it may also inhibit other factors that, for example, play an important role in tissue maintenance and repair. Within this review we focus on articular cartilage, highlighting the complexities and highly regulated processes that are involved in its formation, and the challenges that exist in trying to effectively engineer this tissue. Here we discuss the opportunities that glycosaminoglycans (GAGs) may provide in advancing this important area of regenerative medicine, placing emphasis on the need to move away from the common use of heparin, and instead focus research towards the utility of specific GAG preparations that are able to modulate the activity of growth factors in a more controlled and defined manner, with less off-target effects.
      PubDate: 2017-06-13
      DOI: 10.3390/ph10020054
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 55: Exploring Wound-Healing Genomic
           Machinery with a Network-Based Approach

    • Authors: Francesca Vitali, Simone Marini, Martina Balli, Hanne Grosemans, Maurilio Sampaolesi, Yves Lussier, Maria Cusella De Angelis, Riccardo Bellazzi
      First page: 55
      Abstract: The molecular mechanisms underlying tissue regeneration and wound healing are still poorly understood despite their importance. In this paper we develop a bioinformatics approach, combining biology and network theory to drive experiments for better understanding the genetic underpinnings of wound healing mechanisms and for selecting potential drug targets. We start by selecting literature-relevant genes in murine wound healing, and inferring from them a Protein-Protein Interaction (PPI) network. Then, we analyze the network to rank wound healing-related genes according to their topological properties. Lastly, we perform a procedure for in-silico simulation of a treatment action in a biological pathway. The findings obtained by applying the developed pipeline, including gene expression analysis, confirms how a network-based bioinformatics method is able to prioritize candidate genes for in vitro analysis, thus speeding up the understanding of molecular mechanisms and supporting the discovery of potential drug targets.
      PubDate: 2017-06-21
      DOI: 10.3390/ph10020055
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 56: The Beginning and Development of the
           Theranostic Approach in Nuclear Medicine, as Exemplified by the
           Radionuclide Pair 86Y and 90Y

    • Authors: Frank Rösch, Hans Herzog, Syed Qaim
      First page: 56
      Abstract: In the context of radiopharmacy and molecular imaging, the concept of theranostics entails a therapy-accompanying diagnosis with the aim of a patient-specific treatment. Using the adequate diagnostic radiopharmaceutical, the disease and the state of the disease are verified for an individual patient. The other way around, it verifies that the radiopharmaceutical in hand represents a target-specific and selective molecule: the “best one” for that individual patient. Transforming diagnostic imaging into quantitative dosimetric information, the optimum radioactivity (expressed in maximum radiation dose to the target tissue and tolerable dose to healthy organs) of the adequate radiotherapeutical is applied to that individual patient. This theranostic approach in nuclear medicine is traced back to the first use of the radionuclide pair 86Y/90Y, which allowed a combination of PET and internal radiotherapy. Whereas the β-emitting therapeutic radionuclide 90Y (t½ = 2.7 d) had been available for a long time via the 90Sr/90Y generator system, the β+ emitter 86Y (t½ = 14.7 h) had to be developed for medical application. A brief outline of the various aspects of radiochemical and nuclear development work (nuclear data, cyclotron irradiation, chemical processing, quality control, etc.) is given. In parallel, the paper discusses the methodology introduced to quantify molecular imaging of 86Y-labelled compounds in terms of multiple and long-term PET recordings. It highlights the ultimate goal of radiotheranostics, namely to extract the radiation dose of the analogue 90Y-labelled compound in terms of mGy or mSv per MBq 90Y injected. Finally, the current and possible future development of theranostic approaches based on different PET and therapy nuclides is discussed.
      PubDate: 2017-06-20
      DOI: 10.3390/ph10020056
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 57: A Short-Term Biological Indicator for
           Long-Term Kidney Damage after Radionuclide Therapy in Mice

    • Authors: Giovanni Pellegrini, Klaudia Siwowska, Stephanie Haller, Daniel Antoine, Roger Schibli, Anja Kipar, Cristina Müller
      First page: 57
      Abstract: Folate receptor (FR)-targeted radionuclide therapy using folate radioconjugates is of interest due to the expression of the FR in a variety of tumor types. The high renal accumulation of radiofolates presents, however, a risk of radionephropathy. A potential option to address this challenge would be to use radioprotectants, such as amifostine. Methods for early detection of kidney damage that—in this case—cannot be predicted based on dose estimations, would facilitate the development of novel therapies. The aim of this study was, therefore, to assess potentially changing levels of plasma and urine biomarkers and to determine DNA damage at an early stage after radiofolate application. The identification of an early indicator for renal damage in mice would be useful since histological changes become apparent only several months after treatment. Mice were injected with different quantities of 177Lu-folate (10 MBq, 20 MBq and 30 MBq), resulting in mean absorbed kidney doses of ~23 Gy, ~46 Gy and ~69 Gy, respectively, followed by euthanasia two weeks (>85% of the mean renal radiation dose absorbed) or three months later. Whereas all investigated biomarkers remained unchanged, the number of γ-H2AX-positive nuclei in the renal cortex showed an evident dose-dependent increase as compared to control values two weeks after treatment. Comparison with the extent of kidney injury determined by histological changes five to eight months after administration of the same 177Lu-folate activities suggested that the quantitative assessment of double-strand breaks can be used as a biological indicator for long-term radiation effects in the kidneys. This method may, thus, enable faster assessment of radiopharmaceuticals and protective measures by preventing logistically challenging long-term investigations to detect kidney damage.
      PubDate: 2017-06-21
      DOI: 10.3390/ph10020057
      Issue No: Vol. 10, No. 2 (2017)
  • Pharmaceuticals, Vol. 10, Pages 16: In Search of Small Molecule Inhibitors
           Targeting the Flexible CK2 Subunit Interface

    • Authors: Benoît Bestgen, Zakia Belaid-Choucair, Thierry Lomberget, Marc Le Borgne, Odile Filhol, Claude Cochet
      First page: 16
      Abstract: Protein kinase CK2 is a tetrameric holoenzyme composed of two catalytic (α and/or α’) subunits and two regulatory (β) subunits. Crystallographic data paired with fluorescence imaging techniques have suggested that the formation of the CK2 holoenzyme complex within cells is a dynamic process. Although the monomeric CK2α subunit is endowed with a constitutive catalytic activity, many of the plethora of CK2 substrates are exclusively phosphorylated by the CK2 holoenzyme. This means that the spatial and high affinity interaction between CK2α and CK2β subunits is critically important and that its disruption may provide a powerful and selective way to block the phosphorylation of substrates requiring the presence of CK2β. In search of compounds inhibiting this critical protein–protein interaction, we previously designed an active cyclic peptide (Pc) derived from the CK2β carboxy-terminal domain that can efficiently antagonize the CK2 subunit interaction. To understand the functional significance of this interaction, we generated cell-permeable versions of Pc, exploring its molecular mechanisms of action and the perturbations of the signaling pathways that it induces in intact cells. The identification of small molecules inhibitors of this critical interaction may represent the first-choice approach to manipulate CK2 in an unconventional way.
      PubDate: 2017-02-03
      DOI: 10.3390/ph10010016
      Issue No: Vol. 10, No. 1 (2017)
  • Pharmaceuticals, Vol. 10, Pages 18: CK2 in Cancer: Cellular and
           Biochemical Mechanisms and Potential Therapeutic Target

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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