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Journal Cover
Pharmaceuticals
Journal Prestige (SJR): 1.293
Citation Impact (citeScore): 4
Number of Followers: 4  

  This is an Open Access Journal Open Access journal
ISSN (Print) 1424-8247
Published by MDPI Homepage  [202 journals]
  • Pharmaceuticals, Vol. 11, Pages 31: Computational Modelling of Large Scale
           Phage Production Using a Two-Stage Batch Process

    • Authors: Konrad Krysiak-Baltyn, Gregory Martin, Sally Gras
      First page: 31
      Abstract: Cost effective and scalable methods for phage production are required to meet an increasing demand for phage, as an alternative to antibiotics. Computational models can assist the optimization of such production processes. A model is developed here that can simulate the dynamics of phage population growth and production in a two-stage, self-cycling process. The model incorporates variable infection parameters as a function of bacterial growth rate and employs ordinary differential equations, allowing application to a setup with multiple reactors. The model provides simple cost estimates as a function of key operational parameters including substrate concentration, feed volume and cycling times. For the phage and bacteria pairing examined, costs and productivity varied by three orders of magnitude, with the lowest cost found to be most sensitive to the influent substrate concentration and low level setting in the first vessel. An example case study of phage production is also presented, showing how parameter values affect the production costs and estimating production times. The approach presented is flexible and can be used to optimize phage production at laboratory or factory scale by minimizing costs or maximizing productivity.
      Citation: Pharmaceuticals
      PubDate: 2018-04-08
      DOI: 10.3390/ph11020031
      Issue No: Vol. 11, No. 2 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 32: Antibody-Drug Conjugates for Cancer
           Therapy: Chemistry to Clinical Implications

    • Authors: Nirnoy Dan, Saini Setua, Vivek Kashyap, Sheema Khan, Meena Jaggi, Murali Yallapu, Subhash Chauhan
      First page: 32
      Abstract: Chemotherapy is one of the major therapeutic options for cancer treatment. Chemotherapy is often associated with a low therapeutic window due to its poor specificity towards tumor cells/tissues. Antibody-drug conjugate (ADC) technology may provide a potentially new therapeutic solution for cancer treatment. ADC technology uses an antibody-mediated delivery of cytotoxic drugs to the tumors in a targeted manner, while sparing normal cells. Such a targeted approach can improve the tumor-to-normal tissue selectivity and specificity in chemotherapy. Considering its importance in cancer treatment, we aim to review recent efforts for the design and development of ADCs. ADCs are mainly composed of an antibody, a cytotoxic payload, and a linker, which can offer selectivity against tumors, anti-cancer activity, and stability in systemic circulation. Therefore, we have reviewed recent updates and principal considerations behind ADC designs, which are not only based on the identification of target antigen, cytotoxic drug, and linker, but also on the drug-linker chemistry and conjugation site at the antibody. Our review focuses on site-specific conjugation methods for producing homogenous ADCs with constant drug-antibody ratio (DAR) in order to tackle several drawbacks that exists in conventional conjugation methods.
      Citation: Pharmaceuticals
      PubDate: 2018-04-09
      DOI: 10.3390/ph11020032
      Issue No: Vol. 11, No. 2 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 33: Phytochemical Study of the Ecuadorian
           Species Lepechinia mutica (Benth.) Epling and High Antifungal Activity of
           Carnosol against Pyricularia oryzae

    • Authors: Jorge Ramírez, Gianluca Gilardoni, Erika Ramón, Solveig Tosi, Anna Maria Picco, Carlo Bicchi, Giovanni Vidari
      First page: 33
      Abstract: The plant Lepechinia mutica (Benth.) Epling (family Lamiaceae) is endemic to Ecuador. In the present study, we report some major non-volatile secondary metabolites from the leaves and the chemistry of the essential oil distilled from the flowers. The main identified compounds were carnosol, viridiflorol, ursolic acid, oleanolic acid, chrysothol, and 5-hydroxy-4′,7-dimethoxy flavone. Their structures were determined by X-ray diffraction and NMR and MS techniques. The essential oil showed a chemical composition similar to that distilled from the leaves, but with some qualitative and quantitative differences regarding several minor compounds. The main constituents (>4%) were: δ-3-carene (24.23%), eudesm-7(11)-en-4-ol (13.02%), thujopsan-2-α-ol (11.90%), β-pinene (7.96%), valerianol (5.19%), and co-eluting limonene and β-phellandrene (4.47%). The volatile fraction was also submitted to enantioselective analysis on a β-cyclodextrin column, obtaining the separation and identification of the enantiomers for α-thujene, β-pinene, sabinene, α-phellandrene, limonene and β-phellandrene. Furthermore, the anti-fungal activity of non-volatile secondary metabolites was tested in vitro, with carnosol resulting in being very active against the “blast disease” caused by the fungus Pyricularia oryzae.
      Citation: Pharmaceuticals
      PubDate: 2018-04-19
      DOI: 10.3390/ph11020033
      Issue No: Vol. 11, No. 2 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 34: Enhancing Whole Phage Therapy and
           Their Derived Antimicrobial Enzymes through Complex Formulation

    • Authors: Callum J. Cooper, Shazeeda Koonjan, Anders S. Nilsson
      First page: 34
      Abstract: The resurgence of research into phage biology and therapy is, in part, due to the increasing need for novel agents to treat multidrug-resistant infections. Despite a long clinical history in Eastern Europe and initial success within the food industry, commercialized phage products have yet to enter other sectors. This relative lack of success is, in part, due to the inherent biological limitations of whole phages. These include (but are not limited to) reaching target sites at sufficiently high concentrations to establish an infection which produces enough progeny phages to reduce the bacterial population in a clinically meaningful manner and the limited host range of some phages. Conversely, parallels can be drawn between antimicrobial enzymes derived from phages and conventional antibiotics. In the current article the biological limitations of whole phage-based therapeutics and their derived antimicrobial enzymes will be discussed. In addition, the ability of more complex formulations to address these issues, in the context of medical and non-medical applications, will also be included.
      Citation: Pharmaceuticals
      PubDate: 2018-04-19
      DOI: 10.3390/ph11020034
      Issue No: Vol. 11, No. 2 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 35: Research Progress on Rolling Circle
           Amplification (RCA)-Based Biomedical Sensing

    • Authors: Lide Gu, Wanli Yan, Le Liu, Shujun Wang, Xu Zhang, Mingsheng Lyu
      First page: 35
      Abstract: Enhancing the limit of detection (LOD) is significant for crucial diseases. Cancer development could take more than 10 years, from one mutant cell to a visible tumor. Early diagnosis facilitates more effective treatment and leads to higher survival rate for cancer patients. Rolling circle amplification (RCA) is a simple and efficient isothermal enzymatic process that utilizes nuclease to generate long single stranded DNA (ssDNA) or RNA. The functional nucleic acid unit (aptamer, DNAzyme) could be replicated hundreds of times in a short period, and a lower LOD could be achieved if those units are combined with an enzymatic reaction, Surface Plasmon Resonance, electrochemical, or fluorescence detection, and other different kinds of biosensor. Multifarious RCA-based platforms have been developed to detect a variety of targets including DNA, RNA, SNP, proteins, pathogens, cytokines, micromolecules, and diseased cells. In this review, improvements in using the RCA technique for medical biosensors and biomedical applications were summarized and future trends in related research fields described.
      Citation: Pharmaceuticals
      PubDate: 2018-04-21
      DOI: 10.3390/ph11020035
      Issue No: Vol. 11, No. 2 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 36: NUC041, a Prodrug of the DNA
           Methytransferase Inhibitor 5-aza-2′,2′-Difluorodeoxycytidine (NUC013),
           Leads to Tumor Regression in a Model of Non-Small Cell Lung Cancer

    • Authors: Richard Daifuku, Sheila Grimes, Murray Stackhouse
      First page: 36
      Abstract: 5-aza-2′,2′-difluorodeoxycytidine (NUC013) has been shown to be significantly safer and more effective than decitabine in xenograft models of human leukemia and colon cancer. However, it suffers from a similar short half-life as other DNA methyltransferase inhibitors with a 5-azacytosine base, which is problematic for nucleosides that primarily target tumor cells in S phase. Because of the relative instability of 5-azanucleosides, a prodrug approach was developed to improve the pharmacology of NUC013. NUC013 was conjugated with trimethylsilanol (TMS) at the 3′ and 5′ position of the sugar, rendering the molecule hydrophobic and producing 3′,5′-di-trimethylsilyl-2′,2′-difluoro-5-azadeoxycytidine (NUC041). NUC041 was designed to be formulated in a hydrophobic vehicle, protecting it from deamination and hydrolysis. In contact with blood, the TMS moieties are readily hydrolyzed to release NUC013. The half-life of NUC013 administered intravenously in mice is 20.1 min, while that of NUC013 derived from intramuscular NUC041 formulated in a pegylated-phospholipid depot is 3.4 h. In a NCI-H460 xenograft of non-small cell lung cancer, NUC013 was shown to significantly inhibit tumor growth and improve survival. Treatment with NUC041 also led to significant tumor growth inhibition. However, NUC041-treated mice had significantly more tumors ulcerate than either NUC013 treated mice or saline control mice, and such ulceration occurred at significantly lower tumor volumes. In these nude mice, tumor regression was likely mediated by the derepression of the tumor suppressor gene p53 and resultant activation of natural killer (NK) cells.
      Citation: Pharmaceuticals
      PubDate: 2018-04-23
      DOI: 10.3390/ph11020036
      Issue No: Vol. 11, No. 2 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 37: Mechanism of the Dual Activities of
           Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone
           Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency

    • Authors: Mónica Fernández-Cancio, Núria Camats, Christa E. Flück, Adam Zalewski, Bernhard Dick, Brigitte M. Frey, Raquel Monné, Núria Torán, Laura Audí, Amit V. Pandey
      First page: 37
      Abstract: The CYP17A1 gene regulates sex steroid biosynthesis in humans through 17α-hydroxylase/17,20 lyase activities and is a target of anti-prostate cancer drug abiraterone. In a 46, XY patient with female external genitalia, together with a loss of function mutation S441P, we identified a novel missense mutation V366M at the catalytic center of CYP17A1 which preferentially impaired 17,20 lyase activity. Kinetic experiments with bacterially expressed proteins revealed that V366M mutant enzyme can bind and metabolize pregnenolone to 17OH-pregnenolone, but 17OH-pregnenolone binding and conversion to dehydroepiandrosterone (DHEA) was impaired, explaining the patient’s steroid profile. Abiraterone could not bind and inhibit the 17α-hydroxylase activity of the CYP17A1-V366M mutant. Molecular dynamics (MD) simulations showed that V366M creates a “one-way valve” and suggests a mechanism for dual activities of human CYP17A1 where, after the conversion of pregnenolone to 17OH-pregnenolone, the product exits the active site and re-enters for conversion to dehydroepiandrosterone. The V366M mutant also explained the effectiveness of the anti-prostate cancer drug abiraterone as a potent inhibitor of CYP17A1 by binding tightly at the active site in the WT enzyme. The V366M is the first human mutation to be described at the active site of CYP17A1 that causes isolated 17,20 lyase deficiency. Knowledge about the specificity of CYP17A1 activities is of importance for the development of treatments for polycystic ovary syndrome and inhibitors for prostate cancer therapy.
      Citation: Pharmaceuticals
      PubDate: 2018-04-29
      DOI: 10.3390/ph11020037
      Issue No: Vol. 11, No. 2 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 38: Diagnostic Accuracy of Protein
           Glycation Sites in Long-Term Controlled Patients with Type 2 Diabetes
           Mellitus and Their Prognostic Potential for Early Diagnosis

    • Authors: Sandro Spiller, Yichao Li, Matthias Blüher, Lonnie Welch, Ralf Hoffmann
      First page: 38
      Abstract: Current screening tests for type 2 diabetes mellitus (T2DM) identify less than 50% of undiagnosed T2DM patients and provide no information about how the disease will develop in prediabetic patients. Here, twenty-nine protein glycation sites were quantified after tryptic digestion of plasma samples at the peptide level using tandem mass spectrometry and isotope-labelled peptides as internal standard. The glycation degrees were determined in three groups, i.e., 48 patients with a duration of T2DM exceeding ten years, 48 non-diabetic individuals matched for gender, BMI, and age, and 20 prediabetic men. In long-term controlled diabetic patients, 27 glycated peptides were detected at significantly higher levels, providing moderate diagnostic accuracies (ACCs) from 61 to 79%, allowing a subgrouping of patients in three distinct clusters. Moreover, a feature set of one glycated peptides and six established clinical parameters provided an ACC of 95%. The same number of clusters was identified in prediabetic males (ACC of 95%) using a set of eight glycation sites (mostly from serum albumin). All patients present in one cluster showed progression of prediabetic state or advanced towards diabetes in the following five years. Overall, the studied glycation sites appear to be promising biomarkers for subgrouping prediabetic patients to estimate their risk for the development of T2DM.
      Citation: Pharmaceuticals
      PubDate: 2018-04-30
      DOI: 10.3390/ph11020038
      Issue No: Vol. 11, No. 2 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 39: Iron Release from Soybean Seed
           Ferritin Induced by Cinnamic Acid Derivatives

    • Authors: Xuejiao Sha, Hai Chen, Jingsheng Zhang, Guanghua Zhao
      First page: 39
      Abstract: Plant ferritin represents a novel class of iron supplement, which widely co-exists with phenolic acids in a plant diet. However, there are few reports on the effect of these phenolic acids on function of ferritin. In this study, we demonstrated that cinnamic acid derivatives, as widely occurring phenolic acids, can induce iron release from holo soybean seed ferritin (SSF) in a structure-dependent manner. The ability of the iron release from SSF by five cinnamic acids follows the sequence of Cinnamic acid > Chlorogenic acid > Ferulic acid > p-Coumaric acid > Trans-Cinnamic acid. Fluorescence titration in conjunction with dialysis results showed that all of these five compounds have a similar, weak ability to bind with protein, suggesting that their protein-binding ability is not related to their iron release activity. In contrast, both Fe2+-chelating activity and reducibility of these cinnamic acid derivatives are in good agreement with their ability to induce iron release from ferritin. These studies indicate that cinnamic acid and its derivatives could have a negative effect on iron stability of holo soybean seed ferritin in diet, and the Fe2+-chelating activity and reducibility of cinnamic acid and its derivatives have strong relations to the iron release of soybean seed ferritin.
      Citation: Pharmaceuticals
      PubDate: 2018-05-04
      DOI: 10.3390/ph11020039
      Issue No: Vol. 11, No. 2 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 40: Synthesis and Structure-Activity
           Relationships of (−)-cis-N-Normetazocine-Based LP1 Derivatives

    • Authors: Lorella Pasquinucci, Carmela Parenti, Emanuele Amata, Zafiroula Georgoussi, Paschalina Pallaki, Valeria Camarda, Girolamo Calò, Emanuela Arena, Lucia Montenegro, Rita Turnaturi
      First page: 40
      Abstract: (−)-cis-N-Normetazocine represents a rigid scaffold able to mimic the tyramine moiety of endogenous opioid peptides, and the introduction of different N-substituents influences affinity and efficacy of respective ligands at MOR (mu opioid receptor), DOR (delta opioid receptor), and KOR (kappa opioid receptor). We have previously identified LP1, a MOR/DOR multitarget opioid ligand, with an N-phenylpropanamido substituent linked to (−)-cis-N-Normetazocine scaffold. Herein, we report the synthesis, competition binding and calcium mobilization assays of new compounds 10–16 that differ from LP1 by the nature of the N-substituent. In radioligand binding experiments, the compounds 10–13, featured by an electron-withdrawing or electron-donating group in the para position of phenyl ring, displayed improved affinity for KOR (Ki = 0.85–4.80 μM) in comparison to LP1 (7.5 μM). On the contrary, their MOR and DOR affinities were worse (Ki = 0.18–0.28 μM and Ki = 0.38–1.10 μM, respectively) with respect to LP1 values (Ki = 0.049 and 0.033 μM). Analogous trends was recorded for the compounds 14–16, featured by indoline, tetrahydroquinoline, and diphenylamine functionalities in the N-substituent. In calcium mobilization assays, the compound 10 with a p-fluorophenyl in the N-substituent shared the functional profile of LP1 (pEC50MOR = 7.01), although it was less active. Moreover, the p-methyl- (11) and p-cyano- (12) substituted compounds resulted in MOR partial agonists and DOR/KOR antagonists. By contrast, the derivatives 13–15 resulted as MOR antagonists, and the derivative 16 as a MOR/KOR antagonist (pKBMOR = 6.12 and pKBKOR = 6.11). Collectively, these data corroborated the critical role of the N-substituent in (−)-cis-N-Normetazocine scaffold. Thus, the new synthesized compounds could represent a template to achieve a specific agonist, antagonist, or mixed agonist/antagonist functional profile.
      Citation: Pharmaceuticals
      PubDate: 2018-05-05
      DOI: 10.3390/ph11020040
      Issue No: Vol. 11, No. 2 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 41: Mitoxantrone is More Toxic than
           Doxorubicin in SH-SY5Y Human Cells: A ‘Chemobrain’ In Vitro Study

    • Authors: Daniela Almeida, Rita Pinho, Verónica Correia, Jorge Soares, Maria de Lourdes Bastos, Félix Carvalho, João Paulo Capela, Vera Marisa Costa
      First page: 41
      Abstract: The potential neurotoxic effects of anticancer drugs, like doxorubicin (DOX) and mitoxantrone (MTX; also used in multiple sclerosis), are presently important reasons for concern, following epidemiological data indicating that cancer survivors submitted to chemotherapy may suffer cognitive deficits. We evaluated the in vitro neurotoxicity of two commonly used chemotherapeutic drugs, DOX and MTX, and study their underlying mechanisms in the SH-SY5Y human neuronal cell model. Undifferentiated human SH-SY5Y cells were exposed to DOX or MTX (0.13, 0.2 and 0.5 μM) for 48 h and two cytotoxicity assays were performed, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) reduction and the neutral red (NR) incorporation assays. Phase contrast microphotographs, Hoechst, and acridine orange/ethidium bromide stains were performed. Mitochondrial membrane potential was also assessed. Moreover, putative protective drugs, namely the antioxidants N-acetyl-l-cysteine (NAC; 1 mM) and 100 μM tiron, the inhibitor of caspase-3/7, Ac-DEVD-CHO (100 μM), and a protein synthesis inhibitor, cycloheximide (CHX; 10 nM), were tested to prevent DOX- or MTX-induced toxicity. The MTT reduction assay was also done in differentiated SH-SY5Y cells following exposure to 0.2 μM DOX or MTX. MTX was more toxic than DOX in both cytotoxicity assays and according to the morphological analyses. MTX also evoked a higher number of apoptotic nuclei than DOX. Both drugs, at the 0.13 μM concentration, caused mitochondrial membrane potential depolarization after a 48-h exposure. Regarding the putative neuroprotectors, 1 mM NAC was not able to prevent the cytotoxicity caused by either drug. Notwithstanding, 100 μM tiron was capable of partially reverting MTX-induced cytotoxicity in the NR uptake assay. One hundred μM Ac-DEVD-CHO and 10 nM cycloheximide (CHX) also partially prevented the toxicity induced by DOX in the NR uptake assay. MTX was more toxic than DOX in differentiated SH-SY5Y cells, while MTX had similar toxicity in differentiated and undifferentiated SH-SY5Y cells. In fact, MTX was the most neurotoxic drug tested and the mechanisms involved seem dissimilar among drugs. Thus, its toxicity mechanisms need to be further investigated as to determine the putative neurotoxicity for multiple sclerosis and cancer patients.
      Citation: Pharmaceuticals
      PubDate: 2018-05-05
      DOI: 10.3390/ph11020041
      Issue No: Vol. 11, No. 2 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 42: 2017 FDA Peptide Harvest

    • Authors: Othman Al Musaimi, Danah Al Shaer, Beatriz G. de la Torre, Fernando Albericio
      First page: 42
      Abstract: 2017 was an excellent year in terms of new drugs (chemical entities and biologics) approved by the FDA, with a total of 46. In turn, one of the highlights was the number of peptides (six) included in this list. Here, the six peptides are analyzed in terms of chemical structure, synthetic strategy used for their production, source, therapeutic use, and mode of action.
      Citation: Pharmaceuticals
      PubDate: 2018-05-07
      DOI: 10.3390/ph11020042
      Issue No: Vol. 11, No. 2 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 43: Evaluation of Anti-Toxoplasma gondii
           Effect of Ursolic Acid as a Novel Toxoplasmosis Inhibitor

    • Authors: Won Hyung Choi, In Ah Lee
      First page: 43
      Abstract: This study was carried out to evaluate the anti-parasitic effect of ursolic acid against Toxoplasma gondii (T. gondii) that induces toxoplasmosis, particularly in humans. The anti-parasitic effects of ursolic acid against T. gondii-infected cells and T. gondii were evaluated through different specific assays, including immunofluorescence staining and animal testing. Ursolic acid effectively inhibited the proliferation of T. gondii when compared with sulfadiazine, and consistently induced anti-T. gondii activity/effect. In particular, the formation of parasitophorous vacuole membrane (PVM) in host cells was markedly decreased after treating ursolic acid, which was effectively suppressed. Moreover, the survival rate of T. gondii was strongly inhibited in T. gondii group treated with ursolic acid, and then 50% inhibitory concentration (IC50) against T. gondii was measured as 94.62 μg/mL. The T. gondii-infected mice treated with ursolic acid indicated the same survival rates and activity as the normal group. These results demonstrate that ursolic acid causes anti-T. gondii action and effect by strongly blocking the proliferation of T. gondii through the direct and the selective T. gondii-inhibitory ability as well as increases the survival of T. gondii-infected mice. This study shows that ursolic acid has the potential to be used as a promising anti-T. gondii candidate substance for developing effective anti-parasitic drugs.
      Citation: Pharmaceuticals
      PubDate: 2018-05-09
      DOI: 10.3390/ph11020043
      Issue No: Vol. 11, No. 2 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 44: Old Drugs as New Treatments for
           Neurodegenerative Diseases

    • Authors: Fernando Durães, Madalena Pinto, Emília Sousa
      First page: 44
      Abstract: Neurodegenerative diseases are increasing in number, given that the general global population is becoming older. They manifest themselves through mechanisms that are not fully understood, in many cases, and impair memory, cognition and movement. Currently, no neurodegenerative disease is curable, and the treatments available only manage the symptoms or halt the progression of the disease. Therefore, there is an urgent need for new treatments for this kind of disease, since the World Health Organization has predicted that neurodegenerative diseases affecting motor function will become the second-most prevalent cause of death in the next 20 years. New therapies can come from three main sources: synthesis, natural products, and existing drugs. This last source is known as drug repurposing, which is the most advantageous, since the drug’s pharmacokinetic and pharmacodynamic profiles are already established, and the investment put into this strategy is not as significant as for the classic development of new drugs. There have been several studies on the potential of old drugs for the most relevant neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Multiple Sclerosis and Amyotrophic Lateral Sclerosis.
      Citation: Pharmaceuticals
      PubDate: 2018-05-11
      DOI: 10.3390/ph11020044
      Issue No: Vol. 11, No. 2 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 45: Novel N4-Like Bacteriophages of
           Pectobacterium atrosepticum

    • Authors: Colin Buttimer, Hanne Hendrix, Alan Lucid, Horst Neve, Jean-Paul Noben, Charles Franz, Jim O’Mahony, Rob Lavigne, Aidan Coffey
      First page: 45
      Abstract: Pectobacterium atrosepticum is an economically important phytopathogen that is responsible for potato blackleg and soft rot, and for which current control strategies are limited. In this study, stem samples of potato crops exhibiting blackleg were taken from three farms in Co. Cork, Ireland, and they were found to be infected with P. atrosepticum. Three closely related bacteriophages (phages) that are specific to this phytopathogen were isolated and characterized, namely vB_PatP_CB1, vB_PatP_CB3, and vB_PatP_CB4 (abbreviated as CB1, CB3, and CB4). Both CB1 and CB3 were determined to infect 12 strains and CB4 10 strains of the 19 strains of P. atrosepticum tested. Morphology, latent periods, burst sizes, and their stability at various temperatures and pHs were also examined. Genome sequencing of the three phages revealed that they shared a minimum nucleotide identity of 93% with each other. Their genomes exhibited an Enquartavirinae genome organization, possessing several conserved proteins that were associated with phages of this group, like the type species Escherichia virus N4. Tandem electrospray ionization-mass spectrometry (ESI-MS/MS) allowed for the identification of ten structural proteins that form the virion of CB1, six that are conserved in phage N4. Biocontrol experiments demonstrated that the phages suppress soft rot formation upon co-inoculation with P. atrosepticum on whole tubers. The results of this study indicate that CB1 related phages could be good candidates for phage-based control.
      Citation: Pharmaceuticals
      PubDate: 2018-05-14
      DOI: 10.3390/ph11020045
      Issue No: Vol. 11, No. 2 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 46: The Effects of Dabigatran and
           Rivaroxaban on Markers of Polymorphonuclear Leukocyte Activation

    • Authors: Guy Richards, Annette Theron, Gregory Tintinger, Ronald Anderson
      First page: 46
      Abstract: Dabigatran is an oral direct thrombin inhibitor, and rivaroxaban, a factor Xa inhibitor. Dabigatran has been implicated in the etiology of acute coronary syndromes and as these occur following inflammatory changes in the endothelium, we investigated the inflammatory potential of these agents in vitro. In order to do so, polymorphonuclear leukocytes (PMNL) were isolated from heparinized venous blood from non-smoking, healthy adults and exposed to dabigatran or rivaroxaban (0.5–10 µM). Generation of reactive oxygen species (ROS), elastase release, cytosolic Ca2+ fluxes, neutrophil extracellular trap (NET) formation and cell viability were measured using chemiluminescence, spectrophotometric and flow cytometric procedures respectively. However, with the exception of modest inhibitory effects on elastase release, neither agent at concentrations of up to 10 µM affected these markers of PMNL activation. Although no pro-inflammatory effects of dabigatran nor any difference between the two test agents were detected in vitro, the existence of a pro-inflammatory mechanism involving the generation of thrombin during dabigatran therapy cannot be fully excluded.
      Citation: Pharmaceuticals
      PubDate: 2018-05-14
      DOI: 10.3390/ph11020046
      Issue No: Vol. 11, No. 2 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 47: High Concentrations of Sodium Chloride
           Improve Microbicidal Activity of Ibuprofen against Common Cystic Fibrosis
           Pathogens

    • Authors: Adrián Muñoz, Roxana Alasino, Ariel Garro, Valeria Heredia, Néstor García, David Cremonezzi, Dante Beltramo
      First page: 47
      Abstract: Ibuprofen (IBU-H), a widely used anti-inflammatory, also shows a marked antimicrobial effect against several bacterial species, including those involved in cystic fibrosis such as Pseudomona aeruginosa, methicillin resistant Staphylococcus aureus and Burkholderia cepacia complex. Additionally, our results show significant synergy between water soluble Na-ibuprofen (IBU-Na) and ionic strength. Salt concentrations above 0.5 M modify the zeta potential promoting the action of Na-IBU; thus, with 1 M sodium chloride, IBU-Na is ten times more efficient than in the absence of ionic strength, and the minimum effective contact time is reduced from hours to minutes. In short time periods, where neither IBU-Na nor controls with 1 M NaCl show activity, the combination of both leads to a reduction in the bacterial load. We also analyzed whether the changes caused by salt on the bacterial membrane also promoted the activity of other microbicide compounds used in cystic fibrosis like gentamicin, tobramycin and phosphomycin. The results show that the presence of ionic strength only enhanced the bactericidal activity of the amphipathic molecule of IBU-Na. In this respect, the effect of saline concentration was also reflected in the surface properties of IBU-Na, where, in addition to the clear differences observed between 145 mM and 1 M, singular behaviors were also found, different in each condition. The combination of anti-inflammatory activity and this improved bactericidal effect of Na-IBU in hypertonic solution provides a new alternative for the treatment of respiratory infections of fibrotic patients based on known and widely used compounds.
      Citation: Pharmaceuticals
      PubDate: 2018-05-17
      DOI: 10.3390/ph11020047
      Issue No: Vol. 11, No. 2 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 48: The Role of TRP Channels in the
           Metastatic Cascade

    • Authors: Benedikt Fels, Etmar Bulk, Zoltán Pethő, Albrecht Schwab
      First page: 48
      Abstract: A dysregulated cellular Ca2+ homeostasis is involved in multiple pathologies including cancer. Changes in Ca2+ signaling caused by altered fluxes through ion channels and transporters (the transportome) are involved in all steps of the metastatic cascade. Cancer cells thereby “re-program” and “misuse” the cellular transportome to regulate proliferation, apoptosis, metabolism, growth factor signaling, migration and invasion. Cancer cells use their transportome to cope with diverse environmental challenges during the metastatic cascade, like hypoxic, acidic and mechanical cues. Hence, ion channels and transporters are key modulators of cancer progression. This review focuses on the role of transient receptor potential (TRP) channels in the metastatic cascade. After briefly introducing the role of the transportome in cancer, we discuss TRP channel functions in cancer cell migration. We highlight the role of TRP channels in sensing and transmitting cues from the tumor microenvironment and discuss their role in cancer cell invasion. We identify open questions concerning the role of TRP channels in circulating tumor cells and in the processes of intra- and extravasation of tumor cells. We emphasize the importance of TRP channels in different steps of cancer metastasis and propose cancer-specific TRP channel blockade as a therapeutic option in cancer treatment.
      Citation: Pharmaceuticals
      PubDate: 2018-05-17
      DOI: 10.3390/ph11020048
      Issue No: Vol. 11, No. 2 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 49: A Short Peptide Inhibitor as an
           Activity-Based Probe for Matriptase-2

    • Authors: Martin Mangold, Michael Gütschow, Marit Stirnberg
      First page: 49
      Abstract: Matriptase-2 is a type II transmembrane serine protease and a key regulator of systemic iron homeostasis. Since the activation mechanism and several features of the physiological role of matriptase-2 are not fully understood, there is strong need for analytical tools to perform tasks such as distinguishing active and inactive matriptase-2. For this purpose we present a short biotinylated peptide derivative with a chloromethyl ketone group, biotin-RQRR-CMK, as an activity-based probe for matriptase-2. Biotin-RQRR-CMK was kinetically characterized and exhibited a second-order rate constant of inactivation (kinac/Ki) of 10,800 M−1 s−1 towards the matriptase-2 activity in the supernatant of transfected human embryonic kidney (HEK) cells. Biotin-RQRR-CMK was able to label active matriptase-2, as visualized in western blot experiments. Pretreatment with aprotinin, an active-site directed inhibitor of serine proteases, protected matriptase-2 from the reaction with biotin-RQRR-CMK.
      Citation: Pharmaceuticals
      PubDate: 2018-05-21
      DOI: 10.3390/ph11020049
      Issue No: Vol. 11, No. 2 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 50: Controlled-Deactivation CB1 Receptor
           Ligands as a Novel Strategy to Lower Intraocular Pressure

    • Authors: Sally Miller, Shashank Kulkarni, Alex Ciesielski, Spyros P. Nikas, Ken Mackie, Alexandros Makriyannis, Alex Straiker
      First page: 50
      Abstract: Nearly half a century has passed since the demonstration that cannabis and its chief psychoactive component Δ9-THC lowers intraocular pressure (IOP). Elevated IOP remains the chief hallmark and therapeutic target for glaucoma, a condition that places millions at risk of blindness. It is likely that Δ9-THC exerts much of its IOP-lowering effects via the activation of CB1 cannabinoid receptors. However, the initial promise of CB1 as a target for treating glaucoma has not thus far translated into a credible therapeutic strategy. We have recently shown that blocking monoacylglycerol lipase (MAGL), an enzyme that breaks the endocannabinoid 2-arachidonoyl glycerol (2-AG), substantially lowers IOP. Another strategy is to develop cannabinoid CB1 receptor agonists that are optimized for topical application to the eye. Recently we have reported on a controlled-deactivation approach where the “soft” drug concept of enzymatic deactivation was combined with a “depot effect” that is commonly observed with Δ9-THC and other lipophilic cannabinoids. This approach allowed us to develop novel cannabinoids with a predictable duration of action and is particularly attractive for the design of CB1 activators for ophthalmic use with limited or no psychoactive effects. We have tested a novel class of compounds using a combination of electrophysiology in autaptic hippocampal neurons, a well-characterized model of endogenous cannabinoid signaling, and measurements of IOP in a mouse model. We now report that AM7410 is a reasonably potent and efficacious agonist at CB1 in neurons and that it substantially (30%) lowers IOP for as long as 5 h after a single topical treatment. This effect is absent in CB1 knockout mice. Our results indicate that the direct targeting of CB1 receptors with controlled-deactivation ligands is a viable approach to lower IOP in a murine model and merits further study in other model systems.
      Citation: Pharmaceuticals
      PubDate: 2018-05-22
      DOI: 10.3390/ph11020050
      Issue No: Vol. 11, No. 2 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 51: Side Effects and Interactions of the
           Xanthine Oxidase Inhibitor Febuxostat

    • Authors: Andreas Jordan, Ursula Gresser
      First page: 51
      Abstract: The paper addresses the safety of febuxostat and summarizes reports on side effects and interactions of febuxostat published by the cut-off date (last day of literature search) of 20 March 2018. Publications on side effects and the interactions of febuxostat were considered. Information concerning the occurrence of side effects and interactions in association with the treatment with febuxostat was collected and summarized in the review. The incidence of severe side effects was much less frequent than mild side effects (1.2–3.8% to 20.1–38.7%). The rate and range of febuxostat side effects are low at doses of up to 120 mg and only increase with a daily dose of over 120 mg. The publications reveal no age-dependent increase in side effects for febuxostat. In patients with impaired renal function, no increase in adverse events is described with a dose of up to 120 mg of febuxostat per day. Patients with impaired liver function had no elevated risk for severe side effects. A known allopurinol intolerance increases the risk of skin reactions during treatment with febuxostat by a factor of 3.6. No correlation between treatment with febuxostat and agranulocytosis has been confirmed. Possible interactions with very few medications (principally azathioprine) are known for febuxostat. Febuxostat is well tolerated and a modern and safe alternative to allopurinol therapy.
      Citation: Pharmaceuticals
      PubDate: 2018-05-25
      DOI: 10.3390/ph11020051
      Issue No: Vol. 11, No. 2 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 52: Development and Validation of a Rapid
           High-Performance Liquid Chromatography–Tandem Mass Spectrometric Method
           for Determination of Folic Acid in Human Plasma

    • Authors: Aref Zayed, Rana Bustami, Wafaa Alabsi, Tamam El-Elimat
      First page: 52
      Abstract: There are health concerns associated with increased folic acid intake from fortified food and supplements. Existing analytical methods, however, which can be employed to carry out epidemiological and bioavailability studies for folic acid involve laborious sample preparation and/or lengthy chromatographic analysis. In this paper we describe a simple, rapid, and sensitive high-performance liquid chromatography–electrospray ionisation-tandem mass spectrometry (HPLC–ESI-MS/MS) method for determination of unmetabolised folic acid in human plasma using folic acid-d4 as an internal standard. The method required only a simple sample preparation step of protein precipitation and had a total run time of 3.5 min, which is the shortest run time reported to date for HPLC–MS/MS method employed for quantifying folic acid in plasma. The analytes were separated on a C18 column (3 µm; 50 × 3.00 mm) using an isocratic mobile phase consisting of ammonium acetate (1 mM)-acetic acid-acetonitrile (9.9:0.1:90, v/v/v). The method was fully validated in terms of accuracy, precision, linearity, selectivity, recovery, matrix effect, and stability. The short run time and the minimal sample preparation makes the method a valuable tool for performing high-throughput analyses. To demonstrate the applicability of the method in real conditions, it was applied successfully in a bioavailability study for the determination of unmetabolised folic acid levels in vivo in human plasma after oral administration of folic acid.
      Citation: Pharmaceuticals
      PubDate: 2018-05-27
      DOI: 10.3390/ph11020052
      Issue No: Vol. 11, No. 2 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 53: Phenytoin Cream for the Treatment for
           Neuropathic Pain: Case Series

    • Authors: David J. Kopsky, Jan M. Keppel Hesselink
      First page: 53
      Abstract: BACKGROUND: Neuropathic pain can be disabling, and is often difficult to treat. Within a year, over half of all patients stop taking their prescribed neuropathic pain medication, which is most probably due to side effects or disappointing analgesic results. Therefore, new therapies are needed to alleviate neuropathic pain. As such, topical analgesics could be a new inroad in the treatment of neuropathic pain. In 2014, we developed a new topical formulation containing either phenytoin or sodium phenytoin. After optimization of the formulation, we were able to reach a 10% concentration and combine phenytoin with other co-analgesics in the same base cream. OBJECTIVE: To describe a series of 70 neuropathic pain patients who were treated with phenytoin cream. MATERIAL AND METHODS: Cases treated with phenytoin 5% or 10% creams were gathered. The mean onset of pain relief, the duration of effect, and reduction in pain intensity measured on the 11-point numerical rating scale (NRS) were all studied. A single-blind response test with phenytoin 10% and placebo creams was conducted on 12 patients in order to select responders prior to prescribing the active cream. Plasma phenytoin concentrations were measured in 16 patients. RESULTS: Nine patients applied phenytoin 5% cream, and 61 patients used phenytoin 10% cream. After grouping the effects of all of the patients, the mean onset of pain relief was 16.3 min (SD: 14.8), the mean duration of analgesia was 8.1 h (SD: 9.1), and the mean pain reduction on the NRS was 61.2% (SD: 25.0). The mean pain reduction on the NRS while using phenytoin cream was statistically significant compared with the baseline, with a reduction of 4.5 (CI: 4.0 to 5.0, p < 0.01). The 12 patients on whom a single-blind response test was performed experienced a statistically significant reduction in pain in the area where the phenytoin 10% cream was applied in comparison to the area where the placebo cream was applied (p < 0.01). Thirty minutes after the test application, the mean pain reduction on the NRS in the areas where the phenytoin 10% cream and the placebo cream were applied was 3.3 (CI: 2.3 to 4.4, p < 0.01) and 1.1 (CI: 0.4 to 1.9, p < 0.05), respectively. In all 16 patients, the phenytoin plasma levels were below the limit of detection. So far, no systemic side effects were reported. Two patients only reported local side effects: a transient burning aggravation and skin rash. CONCLUSION: In this case series, the phenytoin cream had reduced neuropathic pain considerably, with a fast onset of analgesic effect.
      Citation: Pharmaceuticals
      PubDate: 2018-05-28
      DOI: 10.3390/ph11020053
      Issue No: Vol. 11, No. 2 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 54: Multidirectional Efficacy of
           Biologically Active Nitro Compounds Included in Medicines

    • Authors: Dorota Olender, Justyna Żwawiak, Lucjusz Zaprutko
      First page: 54
      Abstract: The current concept in searching for new bioactive products, including mainly original active substances with potential application in pharmacy and medicine, is based on compounds with a previously determined structure, well-known properties, and biological activity profile. Nowadays, many commonly used drugs originated from natural sources. Moreover, some natural materials have become the source of leading structures for processing further chemical modifications. Many organic compounds with great therapeutic significance have the nitro group in their structure. Very often, nitro compounds are active substances in many well-known preparations belonging to different groups of medicines that are classified according to their pharmacological potencies. Moreover, the nitro group is part of the chemical structure of veterinary drugs. In this review, we describe many bioactive substances with the nitro group, divided into ten categories, including substances with exciting activity and that are currently undergoing clinical trials.
      Citation: Pharmaceuticals
      PubDate: 2018-05-29
      DOI: 10.3390/ph11020054
      Issue No: Vol. 11, No. 2 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 55: Endocannabinoids in Body Weight
           Control

    • Authors: Henrike Horn, Beatrice Böhme, Laura Dietrich, Marco Koch
      First page: 55
      Abstract: Maintenance of body weight is fundamental to maintain one’s health and to promote longevity. Nevertheless, it appears that the global obesity epidemic is still constantly increasing. Endocannabinoids (eCBs) are lipid messengers that are involved in overall body weight control by interfering with manifold central and peripheral regulatory circuits that orchestrate energy homeostasis. Initially, blocking of eCB signaling by first generation cannabinoid type 1 receptor (CB1) inverse agonists such as rimonabant revealed body weight-reducing effects in laboratory animals and men. Unfortunately, rimonabant also induced severe psychiatric side effects. At this point, it became clear that future cannabinoid research has to decipher more precisely the underlying central and peripheral mechanisms behind eCB-driven control of feeding behavior and whole body energy metabolism. Here, we will summarize the most recent advances in understanding how central eCBs interfere with circuits in the brain that control food intake and energy expenditure. Next, we will focus on how peripheral eCBs affect food digestion, nutrient transformation and energy expenditure by interfering with signaling cascades in the gastrointestinal tract, liver, pancreas, fat depots and endocrine glands. To finally outline the safe future potential of cannabinoids as medicines, our overall goal is to address the molecular, cellular and pharmacological logic behind central and peripheral eCB-mediated body weight control, and to figure out how these precise mechanistic insights are currently transferred into the development of next generation cannabinoid medicines displaying clearly improved safety profiles, such as significantly reduced side effects.
      Citation: Pharmaceuticals
      PubDate: 2018-05-30
      DOI: 10.3390/ph11020055
      Issue No: Vol. 11, No. 2 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 56: Inflammation and Neuro-Immune
           Dysregulations in Autism Spectrum Disorders

    • Authors: Dario Siniscalco, Stephen Schultz, Anna Lisa Brigida, Nicola Antonucci
      First page: 56
      Abstract: Autism Spectrum Disorder (ASD) is characterized by persistent deficits in social communication and interaction and restricted-repetitive patterns of behavior, interests, or activities. Strong inflammation states are associated with ASD. This inflammatory condition is often linked to immune system dysfunction. Several cell types are enrolled to trigger and sustain these processes. Neuro-inflammation and neuro-immune abnormalities have now been established in ASD as key factors in its development and maintenance. In this review, we will explore inflammatory conditions, dysfunctions in neuro-immune cross-talk, and immune system treatments in ASD management.
      Citation: Pharmaceuticals
      PubDate: 2018-06-04
      DOI: 10.3390/ph11020056
      Issue No: Vol. 11, No. 2 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 57: Changing Trends in Computational Drug
           Repositioning

    • Authors: Jaswanth K. Yella, Suryanarayana Yaddanapudi, Yunguan Wang, Anil G. Jegga
      First page: 57
      Abstract: Efforts to maximize the indications potential and revenue from drugs that are already marketed are largely motivated by what Sir James Black, a Nobel Prize-winning pharmacologist advocated—“The most fruitful basis for the discovery of a new drug is to start with an old drug”. However, rational design of drug mixtures poses formidable challenges because of the lack of or limited information about in vivo cell regulation, mechanisms of genetic pathway activation, and in vivo pathway interactions. Hence, most of the successfully repositioned drugs are the result of “serendipity”, discovered during late phase clinical studies of unexpected but beneficial findings. The connections between drug candidates and their potential adverse drug reactions or new applications are often difficult to foresee because the underlying mechanism associating them is largely unknown, complex, or dispersed and buried in silos of information. Discovery of such multi-domain pharmacomodules—pharmacologically relevant sub-networks of biomolecules and/or pathways—from collection of databases by independent/simultaneous mining of multiple datasets is an active area of research. Here, while presenting some of the promising bioinformatics approaches and pipelines, we summarize and discuss the current and evolving landscape of computational drug repositioning.
      Citation: Pharmaceuticals
      PubDate: 2018-06-05
      DOI: 10.3390/ph11020057
      Issue No: Vol. 11, No. 2 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 58: TRPM Family Channels in Cancer

    • Authors: Aline Hantute-Ghesquier, Aurélien Haustrate, Natalia Prevarskaya, V’yacheslav Lehen’kyi
      First page: 58
      Abstract: Members of the TRPM (“Melastatin”) family fall into the subclass of the TRP channels having varying permeability to Ca2+ and Mg2+, with three members of the TRPM family being chanzymes, which contain C-terminal enzyme domains. The role of different TRPM members has been shown in various cancers such as prostate cancer for mostly TRPM8 and TRPM2, breast cancer for mostly TRPM2 and TRPM7, and pancreatic cancer for TRPM2/7/8 channels. The role of TRPM5 channels has been shown in lung cancer, TRPM1 in melanoma, and TRPM4 channel in prostate cancer as well. Thus, the TRPM family of channels may represent an appealing target for the anticancer therapy.
      Citation: Pharmaceuticals
      PubDate: 2018-06-07
      DOI: 10.3390/ph11020058
      Issue No: Vol. 11, No. 2 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 59: Synthesis, Evaluation of Cytotoxicity
           and Molecular Docking Studies of the 7-Acetamido Substituted
           2-Aryl-5-bromo-3-trifluoroacetylindoles as Potential Inhibitors of Tubulin
           Polymerization

    • Authors: Malose J. Mphahlele, Nishal Parbhoo
      First page: 59
      Abstract: The 3-trifluoroacetyl–substituted 7-acetamido-2-aryl-5-bromoindoles 5a–h were prepared and evaluated for potential antigrowth effect in vitro against human lung cancer (A549) and cervical cancer (HeLa) cells and for the potential to inhibit tubulin polymerization. The corresponding intermediates, namely, the 3-unsubstituted 7-acetyl-2-aryl-5-bromoindole 2a–d and 7-acetamido-2-aryl-5-bromoindole 4a–d were included in the assays in order to correlate both structural variations and cytotoxicity. No cytotoxicity was observed for compounds 2a–d and their 3-trifluoroacetyl–substituted derivatives 5a–d against both cell lines. The 7-acetamido derivatives 4–d exhibited modest cytotoxicity against both cell lines. All of the 3-trifluoroacetyl–substituted 7-acetamido-2-aryl-5-bromoindoles 5e–h were found to be more active against both cell lines when compared to the chemotherapeutic drug, Melphalan. The most active compound, 5g, induced programmed cell death (apoptosis) in a caspase-dependent manner for both A549 and HeLa cells. Compounds 5e–h were found to significantly inhibit tubulin polymerization against indole-3-carbinol and colchicine as reference standards. Molecular docking of 5g into the colchicine-binding site suggests that the compounds bind to tubulin by different type of interactions including pi-alkyl, amide-pi stacked and alkyl interactions as well as hydrogen bonding with the protein residues to elicit anticancer activity.
      Citation: Pharmaceuticals
      PubDate: 2018-06-11
      DOI: 10.3390/ph11020059
      Issue No: Vol. 11, No. 2 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 60: Parallel Evolution of Host-Attachment
           Proteins in Phage PP01 Populations Adapting to Escherichia coli O157:H7

    • Authors: Chidiebere Akusobi, Benjamin K. Chan, Elizabeth S.C.P. Williams, John E. Wertz, Paul E. Turner
      First page: 60
      Abstract: The emergence of antibiotic resistance has sparked interest in phage therapy, which uses virulent phages as antibacterial agents. Bacteriophage PP01 has been studied for potential bio-control of Escherichia coli O157:H7, its natural host, but in the laboratory, PP01 can be inefficient at killing this bacterium. Thus, the goal of this study was to improve the therapeutic potential of PP01 through short-term experimental evolution. Four replicate populations of PP01 were serially passaged 21 times on non-evolving E. coli O157:H7 with the prediction that the evolved phage populations would adsorb faster and more efficiently kill the host bacteria. Dead-cell adsorption assays and in vitro killing assays confirmed that evolved viruses improved their adsorption ability on E. coli O157:H7, and adapted to kill host bacteria faster than the wildtype ancestor. Sequencing of candidate tail-fiber genes revealed that the phage populations evolved in parallel; the lineages shared two point mutations in gp38 that encodes a host recognition protein, and surprisingly shared a ~600 bp deletion in gp37 that encodes the distal tail fibers. In contrast, no mutations were observed in the gp12 gene encoding PP01’s short tail fibers. We discuss the functional role of the observed mutations, including the possible adaptive role of the evolved deletions. This study demonstrates how experimental evolution can be used to select for viral traits that improve phage attack of an important bacterial pathogen, and that the molecular targets of selection include loci contributing to cell attachment and phage virulence.
      Citation: Pharmaceuticals
      PubDate: 2018-06-20
      DOI: 10.3390/ph11020060
      Issue No: Vol. 11, No. 2 (2018)
       
  • 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
           Nucleosides

    • 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
           Plasticity

    • 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 (www.sciforum.net/conference/ecmc-3). 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 20: Antimicrobial Peptides for Topical
           Treatment of Osteomyelitis and Implant-Related Infections: Study in the
           Spongy Bone

    • Authors: Pavel Melicherčík, Ondřej Nešuta, Václav Čeřovský
      First page: 20
      Abstract: We examined the benefits of short linear α-helical antimicrobial peptides (AMPs) invented in our laboratory for treating bone infection and preventing microbial biofilm formation on model implants due to causative microorganisms of osteomyelitis. For this purpose, we introduced a model of induced osteomyelitis that utilizes human femur heads obtained from the hospital after their replacement with artificial prostheses. We found that the focus of the infection set up in the spongy part of this bone treated with AMP-loaded calcium phosphate cement was eradicated much more effectively than was the focus treated with antibiotics such as vancomycin or gentamicin loaded into the same cement. This contradicts the minimum inhibitory concentrations (MIC) values of AMPs and antibiotics against some bacterial strains obtained in standard in vitro assays. The formation of microbial biofilm on implants made from poly(methylmethacrylate)-based bone cement loaded with AMP was evaluated after the implants’ removal from the infected bone sample. AMPs loaded in such model implants prevented microbial adhesion and subsequent formation of bacterial biofilm on their surface. Biofilms did form, on the other hand, on control implants made from the plain cement when these were implanted into the same infected bone sample. These results of the experiments performed in human bone tissue highlight the clinical potential of antimicrobial peptides for use in treating and preventing osteomyelitis caused by resistant pathogens.
      Citation: Pharmaceuticals
      PubDate: 2018-02-16
      DOI: 10.3390/ph11010020
      Issue No: Vol. 11, No. 1 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 21: Pilocarpine-Induced Status Epilepticus
           Is Associated with P-Glycoprotein Induction in Cardiomyocytes,
           Electrocardiographic Changes, and Sudden Death

    • Authors: Jerónimo Auzmendi, Bruno Buchholz, Jimena Salguero, Carlos Cañellas, Jazmín Kelly, Paula Men, Marcela Zubillaga, Alicia Rossi, Amalia Merelli, Ricardo J. Gelpi, Alberto J. Ramos, Alberto Lazarowski
      First page: 21
      Abstract: Sudden unexpected death in epilepsy (SUDEP) is the major cause of death in those patients suffering from refractory epilepsy (RE), with a 24-fold higher risk relative to the normal population. SUDEP risk increases with seizure frequency and/or seizure-duration as in RE and Status Epilepticus (SE). P-glycoprotein (P-gp), the product of the multidrug resistant ABCB1-MDR-1 gene, is a detoxifying pump that extrudes drugs out of the cells and can confer pharmacoresistance to the expressing cells. Neurons and cardiomyocytes normally do not express P-gp, however, it is overexpressed in the brain of patients or in experimental models of RE and SE. P-gp was also detected after brain or cardiac hypoxia. We have previously demonstrated that repetitive pentylenetetrazole (PTZ)-induced seizures increase P-gp expression in the brain, which is associated with membrane depolarization in the hippocampus, and in the heart, which is associated with fatal SE. SE can produce hypoxic-ischemic altered cardiac rhythm (HIACR) and severe arrhythmias, and both are related with SUDEP. Here, we investigate whether SE induces the expression of hypoxia-inducible transcription factor (HIF)-1α and P-gp in cardiomyocytes, which is associated with altered heart rhythm, and if these changes are related with the spontaneous death rate. SE was induced in Wistar rats once a week for 3 weeks, by lithium-pilocarpine-paradigm. Electrocardiograms, HIF-1α, and P-gp expression in cardiomyocytes, were evaluated in basal conditions and 72 h after SE. All spontaneous deaths occurred 48 h after each SE was registered. We observed that repeated SE induced HIF-1α and P-gp expression in cardiomyocytes, electrocardiographic (ECG) changes, and a high rate of spontaneous death. Our results suggest that the highly accumulated burden of convulsive stress results in a hypoxic heart insult, where P-gp expression may play a depolarizing role in cardiomyocyte membranes and in the development of the ECG changes, such as QT interval prolongation, that could be related with SUDEP. We postulate that this mechanism could explain, in part, the higher SUDEP risk in patients with RE or SE.
      Citation: Pharmaceuticals
      PubDate: 2018-02-16
      DOI: 10.3390/ph11010021
      Issue No: Vol. 11, No. 1 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 22: A Novel Interaction Between the TLR7
           and a Colchicine Derivative Revealed Through a Computational and
           Experimental Study

    • Authors: Francesco Gentile, Marco Deriu, Khaled Barakat, Andrea Danani, Jack Tuszynski
      First page: 22
      Abstract: The Toll-Like Receptor 7 (TLR7) is an endosomal membrane receptor involved in the innate immune system response. Its best-known small molecule activators are imidazoquinoline derivatives such as imiquimod (R-837) and resiquimod (R-848). Recently, an interaction between R-837 and the colchicine binding site of tubulin was reported. To investigate the possibility of an interaction between structural analogues of colchicine and the TLR7, a recent computational model for the dimeric form of the TLR7 receptor was used to determine a possible interaction with a colchicine derivative called CR42-24, active as a tubulin polymerization inhibitor. The estimated values of the binding energy of this molecule with respect to the TLR7 receptor were comparable to the energies of known binders as reported in a previous study. The binding to the TLR7 was further assessed by introducing genetic transformations in the TLR7 gene in cancer cell lines and exposing them to the compound. A negative shift of the IC50 value in terms of cell growth was observed in cell lines carrying the mutated TLR7 gene. The reported study suggests a possible interaction between TLR7 and a colchicine derivative, which can be explored for rational design of new drugs acting on this receptor by using a colchicine scaffold for additional modifications.
      Citation: Pharmaceuticals
      PubDate: 2018-02-16
      DOI: 10.3390/ph11010022
      Issue No: Vol. 11, No. 1 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 23: A π-Halogen Bond of Dibenzofuranones
           with the Gatekeeper Phe113 in Human Protein Kinase CK2 Leads to Potent
           Tight Binding Inhibitors

    • Authors: Alexander Schnitzler, Andreas Gratz, Andre Bollacke, Michael Weyrich, Uwe Kuckländer, Bernhard Wünsch, Claudia Götz, Karsten Niefind, Joachim Jose
      First page: 23
      Abstract: Human protein kinase CK2 is an emerging target for neoplastic diseases. Potent lead structures for human CK2 inhibitors are derived from dibenzofuranones. Two new derivatives, 7,9-dichloro-1,2-dihydro-8-hydroxy-4-[(4-methoxyphenylamino)-methylene]dibenzo[b,d]furan-3(2H)-one (4a) and (E)-1,3-dichloro-6-[(4-methoxyphenylimino)-methyl]dibenzo[b,d]furan-2,7-diol (5) were tested for inhibition of CK2 and induction of apoptosis in LNCaP cells. Both turned out to be tight binding inhibitors, with IC50 values of 7 nM (4a) and 5 nM (5) and an apparent Ki value of 0.4 nM for both. Compounds 4a and 5 reduced cellular CK2 activity, indicating cell permeability. Cell viability was substantially impaired in LNCaP cells, as well as apoptosis was induced, which was not appearing in non-neoplastic ARPE-19 cells. Co-crystallization of 4a and 5 revealed an unexpected π-halogen bond of the chloro substituent at C9 with the gatekeeper amino acid Phe113, leading to an inverted binding mode in comparison to parent compound 4b, with the Cl at C6 instead, which was co-crystallized as a control. This indicates that the position of the chloro substituent on ring A of the dibenzofuran scaffold is responsible for an inversion of the binding mode that enhances potency.
      Citation: Pharmaceuticals
      PubDate: 2018-02-17
      DOI: 10.3390/ph11010023
      Issue No: Vol. 11, No. 1 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 24: Improved Syntheses of the Mglu5
           Antagonists MMPEP and MTEP Using Sonogashira Cross-Coupling

    • Authors: Boshuai Mu, Linjing Mu, Roger Schibli, Simon Ametamey, Selena Milicevic Sephton
      First page: 24
      Abstract: The Sonogashira cross-coupling, a key step in the syntheses of the mGlu5 antagonists MMPEP and MTEP, provided an improved three-step method for the preparation of MMPEP in 62% overall yield. Using Spartan molecular modeling kit an explanation for the failure to employ analogues method in the synthesis of MTEP was sought. The DFT calculations indicated that meaningful isolated yields were obtained when the HOMO energy of the aryl halide was lower than the HOMO energy of the respective alkyne.
      Citation: Pharmaceuticals
      PubDate: 2018-02-20
      DOI: 10.3390/ph11010024
      Issue No: Vol. 11, No. 1 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 25: Characterization of the Lytic
           Capability of a LysK-Like Endolysin, Lys-phiSA012, Derived from a
           Polyvalent Staphylococcus aureus Bacteriophage

    • Authors: Jumpei Fujiki, Tomohiro Nakamura, Takaaki Furusawa, Hazuki Ohno, Hiromichi Takahashi, Junya Kitana, Masaru Usui, Hidetoshi Higuchi, Yasunori Tanji, Yutaka Tamura, Hidetomo Iwano
      First page: 25
      Abstract: Antibiotic-resistant bacteria (ARB) have spread widely and rapidly, with their increased occurrence corresponding with the increased use of antibiotics. Infections caused by Staphylococcus aureus have a considerable negative impact on human and livestock health. Bacteriophages and their peptidoglycan hydrolytic enzymes (endolysins) have received significant attention as novel approaches against ARB, including S. aureus. In the present study, we purified an endolysin, Lys-phiSA012, which harbors a cysteine/histidine-dependent amidohydrolase/peptidase (CHAP) domain, an amidase domain, and a SH3b cell wall binding domain, derived from a polyvalent S. aureus bacteriophage which we reported previously. We demonstrate that Lys-phiSA012 exhibits high lytic activity towards staphylococcal strains, including methicillin-resistant S. aureus (MRSA). Analysis of deletion mutants showed that only mutants possessing the CHAP and SH3b domains could lyse S. aureus, indicating that lytic activity of the CHAP domain depended on the SH3b domain. The presence of at least 1 mM Ca2+ and 100 µM Zn2+ enhanced the lytic activity of Lys-phiSA012 in a turbidity reduction assay. Furthermore, a minimum inhibitory concentration (MIC) assay showed that the addition of Lys-phiSA012 decreased the MIC of oxacillin. Our results suggest that endolysins are a promising approach for replacing current antimicrobial agents and may contribute to the proper use of antibiotics, leading to the reduction of ARB.
      Citation: Pharmaceuticals
      PubDate: 2018-02-24
      DOI: 10.3390/ph11010025
      Issue No: Vol. 11, No. 1 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 26: Semi-Solid and Solid Dosage Forms for
           the Delivery of Phage Therapy to Epithelia

    • Authors: Teagan Brown, Steve Petrovski, Hiu Chan, Michael Angove, Joseph Tucci
      First page: 26
      Abstract: The delivery of phages to epithelial surfaces for therapeutic outcomes is a realistic proposal, and indeed one which is being currently tested in clinical trials. This paper reviews some of the known research on formulation of phages into semi-solid dosage forms such as creams, ointments and pastes, as well as solid dosage forms such as troches (or lozenges and pastilles) and suppositories/pessaries, for delivery to the epithelia. The efficacy and stability of these phage formulations is discussed, with a focus on selection of optimal semi-solid bases for phage delivery. Issues such as the need for standardisation of techniques for formulation as well as for assessment of efficacy are highlighted. These are important when trying to compare results from a range of experiments and across different delivery bases.
      Citation: Pharmaceuticals
      PubDate: 2018-02-26
      DOI: 10.3390/ph11010026
      Issue No: Vol. 11, No. 1 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 27: Glycosaminoglycans and Proteoglycans

    • Authors: Vitor Pomin, Barbara Mulloy
      First page: 27
      Abstract: In this editorial to MDPI Pharmaceuticals special issue “Glycosaminoglycans and Proteoglycans” we describe in outline the common structural features of glycosaminoglycans and the characteristics of proteoglycans, including the intracellular proteoglycan, serglycin, cell-surface proteoglycans, like syndecans and glypicans, and the extracellular matrix proteoglycans, like aggrecan, perlecan, and small leucine-rich proteoglycans. The context in which the pharmaceutical uses of glycosaminoglycans and proteoglycans are presented in this special issue is given at the very end.
      Citation: Pharmaceuticals
      PubDate: 2018-02-27
      DOI: 10.3390/ph11010027
      Issue No: Vol. 11, No. 1 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 28: Low Molecular Weight Chitosan-Coated
           PLGA Nanoparticles for Pulmonary Delivery of Tobramycin for Cystic
           Fibrosis

    • Authors: Nusaiba Al-Nemrawi, Nid’’A Alshraiedeh, Aref Zayed, Bashar Altaani
      First page: 28
      Abstract: (1) Background: Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with Tobramycin were prepared using a solvent-evaporation method. (2) Methods: The NPs were coated with low molecular weight chitosan (LMWC) to enhance the mucoadhesiveness of PLGA-NPs. The following w/w ratios of tobramycin to LMWC were prepared: control (0:0.50), F0 (1:0.25), F0.5 (1:0.5), and F1 (1:1). (3) Results: The results showed that the size of the particles increased from 220.7 nm to 575.77 nm as the concentration of LMWC used in the formulation increased. The surface charge was also affected by the amount of LMWC, where uncoated-PLGA nanoparticles had negative charges (−2.8 mV), while coated-PLGA NPs had positive charges (+33.47 to +50.13 mV). SEM confirmed the size and the spherical homogeneous morphology of the NPs. Coating the NPs with LMWC enhanced the mucoadhesive properties of the NPs and sustained the tobramycin release over two days. Finally, all NPs had antimicrobial activity that increased as the amount of LMWC increased. (4) Conclusion: In conclusion, the formulation of mucoadhesive, controlled-release, tobramycin-LMWC-PLGA nanoparticles for the treatment of P. aeruginosa in cystic fibrosis patients is possible, and their properties could be controlled by controlling the concentration of LMWC.
      Citation: Pharmaceuticals
      PubDate: 2018-03-08
      DOI: 10.3390/ph11010028
      Issue No: Vol. 11, No. 1 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 29: Heterodimer Binding Scaffolds
           Recognition via the Analysis of Kinetically Hot Residues

    • Authors: Ognjen Perišić
      First page: 29
      Abstract: Physical interactions between proteins are often difficult to decipher. The aim of this paper is to present an algorithm that is designed to recognize binding patches and supporting structural scaffolds of interacting heterodimer proteins using the Gaussian Network Model (GNM). The recognition is based on the (self) adjustable identification of kinetically hot residues and their connection to possible binding scaffolds. The kinetically hot residues are residues with the lowest entropy, i.e., the highest contribution to the weighted sum of the fastest modes per chain extracted via GNM. The algorithm adjusts the number of fast modes in the GNM’s weighted sum calculation using the ratio of predicted and expected numbers of target residues (contact and the neighboring first-layer residues). This approach produces very good results when applied to dimers with high protein sequence length ratios. The protocol’s ability to recognize near native decoys was compared to the ability of the residue-level statistical potential of Lu and Skolnick using the Sternberg and Vakser decoy dimers sets. The statistical potential produced better overall results, but in a number of cases its predicting ability was comparable, or even inferior, to the prediction ability of the adjustable GNM approach. The results presented in this paper suggest that in heterodimers at least one protein has interacting scaffold determined by the immovable, kinetically hot residues. In many cases, interacting proteins (especially if being of noticeably different sizes) either behave as a rigid lock and key or, presumably, exhibit the opposite dynamic behavior. While the binding surface of one protein is rigid and stable, its partner’s interacting scaffold is more flexible and adaptable.
      Citation: Pharmaceuticals
      PubDate: 2018-03-16
      DOI: 10.3390/ph11010029
      Issue No: Vol. 11, No. 1 (2018)
       
  • Pharmaceuticals, Vol. 11, Pages 30: Comparison Study of Two Differently
           Clicked 18F-Folates—Lipophilicity Plays a Key Role

    • Authors: Kathrin Kettenbach, Laura Reffert, Hanno Schieferstein, Stefanie Pektor, Raphael Eckert, Matthias Miederer, Frank Rösch, Tobias Ross
      First page: 30
      Abstract: Within the last decade, several folate-based radiopharmaceuticals for Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) have been evaluated; however, there is still a lack of suitable 18F-folates for clinical PET imaging. Herein, we report the synthesis and evaluation of two novel 18F-folates employing strain-promoted and copper-catalyzed click chemistry. Furthermore, the influence of both click-methods on lipophilicity and pharmacokinetics of the 18F-folates was investigated. 18F-Ala-folate and 18F-DBCO-folate were both stable in human serum albumin. In vitro studies proved their high affinity to the folate receptor (FR). The lipophilic character of the strain-promoted clicked 18F-DBCO-folate (logD = 0.6) contributed to a higher non-specific binding in cell internalization studies. In the following in vivo PET imaging studies, FR-positive tumors could not be visualized in a maximum intensity projection images. Compared with 18F-DBCO-folate, 18F-Ala-folate (logD = −1.4), synthesized by the copper-catalyzed click reaction, exhibited reduced lipophilicity, and as a result an improved in vivo performance and a clear-cut visualization of FR-positive tumors. In view of high radiochemical yield, radiochemical purity and favorable pharmacokinetics, 18F-Ala-folate is expected to be a promising candidate for FR-PET imaging.
      Citation: Pharmaceuticals
      PubDate: 2018-03-17
      DOI: 10.3390/ph11010030
      Issue No: Vol. 11, No. 1 (2018)
       
 
 
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