UNITED Scientific Group · point of view a specialist of melatonin, a marker rhythm. Prof. Touitou is a member of the French Academy of Medicine and past President of the French Academy

UNITED Scientific Group

International Conference on

Progressive PharmSciences:Technology, Research and Development

June 19-21, 2017

www.unitedscientificgroup.com/conferences/europps

EuroPPS-2017

VenueBarceló Valencia

Avda. de Francia, 1146023 Valencia, Spain

Notes

Keynote Presentations .............06 - 08

.............09 - 53Featured Presentations

.............54 - 63Poster Presentations

.............64 - 65About Organizer

4 Table of Contents 4


Progressive PharmSciences: Technology, Research and Development

June 19-21, 2017 | Valencia, Spain

« Pharmaceutics

« Pharmacology

« Pharmacognosy

« Pharmaceutical Analysis

« Biopharmaceutics

« Pharmaceutical Chemistry

« Pharmaceutical Biotechnology

« Pharmaceutical Biochemistry

« Pharmaceutical Microbiology

« Industrial Pharmacy

« Physical Pharmacy

« Hospital and Community Pharmacy

« Clinical Pharmacy

« Neuropharmacology

« Psychopharmacology

« Pharmacovigilance

« Pharmacogenetics

« Pharmaceutical Nanotechnology

4 Sessions 4


Progressive PharmSciences: Technology, Research and Development

June 19-21, 2017 | Valencia, Spain

1June 19

Monday

Mitochondrial DNA Over-proliferation and Deletion in the Context of the Drug Development for Neuro-degeneration and Cancer: Link between Cell Signaling, Cancer and Alzheimer Disease via Oxidative Stress Dependent PathwayGjumrakch AlievGALLY International Biomedical Research Consulting LLC, TX, USA The University of Atlanta, GA, USAInstitute of Physiologically Active Compounds Russian Academy of Sciences, RussiaAbstract

Neurodegeneration and cancer are fast becoming the leading causes of age-associated disability, dementia and ultimately death worldwide. Although oxidative stress has been intensely studied, little analysis has been done in chronic oxidative stress-induced mitochondrial models and cell signaling pathway. DNA-overproliferation and/or deletion initiate mitochondrial deregulation causing energy failure, which has been implicated in the pathogenesis of Alzheimer disease (AD), tumor growth, and metastasis. In addition, the overexpression of the cascades initiates the formation and release of large amounts of reactive free radicals [mainly nitric oxide (NO) via the overexpression of NO synthases], which cause the oxidative stress, cellular alterations, and concomitant mitochondrial lesions and decline in normal organ function. One of the key features of tumors is the deficiency in tissue energy that accompanies mitochondrial lesions and formation of the hypoxic smaller sized mitochondria with ultrastructural abnormalities. We theorize that mitochondrial involvement may play a significant role in the etiopathogenesis of cancer. Recently we demonstrate a potential link between AD and cancer, and anticancer drugs are being explored for the inhibition of AD-like pathology in transgenic mice. Severity of the cancer growth, metastasis, and brain pathology

in AD correlate with the degree of mitochondrial ultrastructural abnormalities. Recent advances in the cell-cycle reentry of the terminally differentiated neuronal cells indicate that NO-dependent mitochondrial abnormal activities and mitotic cell division are not the only important pathogenic factors in pathogenesis of cancer and AD, but open a new window for the development of novel treatment strategies for these devastating diseases. The present study explores the intimate, i.e. direct relationship between chronic oxidative stress and mitochondrial damage as a vital life-supporter for cells and/or the microcirculatory systems whose damage occurs before the development of human AD. Further extension of this approach will enable us not only for the better understanding of the blood brain barrier (BBB) homeostasis, which most likely plays a key role in the development of AD and some of forms of the cancer, but also for the development of new and more specific treatment strategies.Biography

Prof. Gjumrakch Aliev, has completed his PhD at the age of 29 years from Moscow State University and Institute of Human Morphology, Russian Academy of Medical Sciences, and postdoctoral studies from University College of London, United Kingdom. He is the President and CEO of “GALLY” International Biomedical Research Consulting LLC, San Antonio, TX, USA a premier Biomedical Research service organization. He also serves as a Professor of Cardiovascular Neuropathology, Geriatrics and Health Sciences and Healthcare Administration at the University of Atlanta, GA, USA, and Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka, 142432, Russia. He has published more than 290 papers in reputed journals and serving as an Editors in Chief and Editorial Board Member of repute.

Keynote Presentations

Progressive PharmSciences: Technology, Research and Development | June 19-21, 2017 | Valencia, Spain 6

Progressive PharmSciences: Technology, Research and Development | June 19-21 | Valencia, Spain 7

Antibiotic Resistance: The Need for a Global StrategyDavid ElderDavid P Elder Consultancy (fGSK), UKAbstract

The development of antibiotic resistance is a major problem for mankind and results in fatal consequences on a daily basis across the globe. There are a number of reasons for this situation including increasing globalization with worldwide travel, health tourism, over use and ineffective use (both in man and animals), and counterfeiting of the antimicrobial drug products we have available currently.

Although there are huge economical, demographic, legal and logistic differences among the global communities, there are also differences regarding the best approach to dealing with antibiotic resistance. However, as resistant bacteria do not respect international borders, there is clearly a need for a global strategy to minimize the spread of antibiotic resistance, to optimize the use of antibiotics, and to facilitate the development of new and effective medications. This presentation provides an insight into the issues and some of the ongoing programs to ensure an effective treatment for the future. The presentation will cover:

• Cost of Developing New Drugs• Target Product Profiles for Novel Antibiotics• Antimicrobial Resistance• Health Tourism• Collaborative Efforts to Address Antimicrobial Resistance and Dispensing

Profiles• Counterfeiting and Falsified Medicines

BiographyProf. Elder has nearly 40 years service within the pharmaceutical industry, with Sterling, Syntex and GSK. He is now an

independent consultant. Dr Elder obtained his PhD in crystallography from the University of Edinburgh. Dr Elder is a visiting professor at King’s College, London. He is a member of the British Pharmacopoeia. He is a member of the Editorial Advisory Board for the Journal of Pharmaceutical Sciences. He has published more than 90 papers in international journals and has given over 100 presentations at international symposia.

The Vicious Circle: Light at Night and Melatonin Suppression, Sleep Alterations, and Clock Disruption Yvan Touitou Fondation Rothschild, FranceAbstract

Light is the major synchronizer of the internal clock located in the suprachiasmatic nuclei of the anterior hypothalamus. Light signal is transmitted from the eye to the clock, then to the pineal gland which produces melatonin, considered as the hand of the clock. Even a weak intensity of light (LEDs, tablets, mobile phones, computers...) is able to block the secretion of melatonin, the hormone of darkness. Light is also able to phase advance or phase delay the circadian system according to the timing of exposure. This Phase Response Curve (PRC) is used to resynchronize the clock in various situations of circadian desynchronization. Exposure to Light at Night (LAN) results in a disruption of the circadian system which is deleterious to health. In industrialized countries, 75 % of the total workforce is estimated to be involved in atypical hours, far from the classical diurnal hours of work. A number of epidemiologic studies, performed mainly on nurses, showed an association between sustained night work (3 to 20 years) and an increased risk of breast cancer. Beside shift workers, adolescents are spending increasing amounts of time online with benefits but also health risks related to excessive use of all kinds of screens resulting in sleep alterations (shortened and delayed) and clock misalignment. The potential mechanisms of the deleterious effects of LAN on health are suppression of melatonin, sleep deprivation and clock disruption. Biography

Dr. Yvan Touitou is a Professor emeritus at the Faculty of Medicine in Paris. He is a chronobiologist working on the Physiopathology and mechanisms of the circadian system. The aim of his current research is focused on the disruption of


the internal clock in shift workers, and in adolescents overusing different types of consoles even late at night. He is from this point of view a specialist of melatonin, a marker rhythm. Prof. Touitou is a member of the French Academy of Medicine and past President of the French Academy of Pharmacy. He was the Editor in Chief of Chronobiology International, the official journal of the International Society of Chronobiology.


A Lignan Induces Lysosomal Dependent Degradation of FoxM1 Protein to Suppress β-catenin Nuclear TranslocationJae-Ha Ryu1*, Guang-Zhi Dong1, Ji Hye Jeong1, Yu-ih Lee1, Young Eun Han1, Jung Sook Shin1, Yoon-Jung Kim1, Raok Jeon1, Young Hwa Kim2, Tae Jun Park2 and Keun Il Kim1

1Sookmyung Women’s University, Korea 2Ajou University, KoreaAbstract

Colon cancer is one of the most common cancers. In this study, we isolated a lignan [(-)-(2R,3R)-1,4-O-diferuloylsecoisolariciresinol, DFS] from Alnus japonica (Betulaceae) and investigated its biological activity and mechanism of action on colon cancer. Treatment with DFS reduced the viability of colon cancer cells and induced cell cycle arrest. Treatment also suppressed β-catenin nuclear location and β-catenin target gene expression through a reduction in FoxM1 protein. To assess the mechanism of the action of DFS, we investigated the effect of DFS on endogenous and exogenous FoxM1 protein degradation in colon cancer cells. DFS-induced FoxM1 protein degradation was suppressed by lysosomal inhibitors, chloroquine and bafilomycin Al, but not by knock-down of proteasomal proteins. The mechanism of DFS for FoxM1 degradation is lysosomal dependent, which was not reported before. Furthermore, we found that FoxM1 degradation was partially lysosomal-dependent under normal conditions. These observations indicate that DFS from A. japonica suppresses colon cancer cell proliferation by reducing β-catenin nuclear translocation. DFS induces lysosomal-dependent FoxM1 protein degradation. This is the first report on the lysosomal degradation of FoxM1 by a small molecule. DFS may be useful in treating cancers that feature the elevated expression of FoxM1.Biography

Dr. Jae-Ha Ryu has completed his PhD at the College of Pharmacy, Seoul National University, Korea in 1989 and postdoctoral studies from National Institute of Health, Maryland, USA. He got academic position in 1992 at College of Pharmacy, Sookmyung Women’s University, Seoul, Korea. He is the director of Research Center for Cell Fate Control (Medical Research Center). His main research interest is to suggest leading compounds from medicinal plants for drug development, especially for the treatment of cancer and various metabolic diseases. He has published 150 papers in reputed journals.

Featured Presentations

Design, Synthesis and Analysis of Novel Flavone Derivatives for Development as Anti-proliferative and Anti-angiogenic AgentsHelen M. I. Osborn*, Divyashree Ravishankar, Kimberly A. Watson and Francesca GrecoUniversity of Reading, UKAbstract

With many cancers showing resistance to current chemotherapies, the search for novel anti-cancer agents is attracting considerable attention1. Natural flavonoids have been identified as useful leads in such programmes2. Herein a broad library of 76 methoxy and hydroxy flavones, and their 4-thio analogues, was constructed using multi-step organic synthesis pathways3. Structure-activity relationships of the flavone derivatives for anti-proliferative activity against the breast cancer cell lines MCF-7 (ER+ve), MCF-7/DX (ER+ve, anthracycline resistant) and MDA-MB-231 (ER-ve) were probed, demonstrating that free hydroxyl groups, and the B-ring phenyl group, were essential for enhanced anti-proliferative activity. Substitution of the 4-C=O functionality with a 4-C=S functionality, and incorporation of electron withdrawing groups at C-4’ of the B-ring also enhanced activity. Preliminary studies also demonstrated that complementary compounds with methoxy susbtituents, and 4-C=O substituents, could inhibit angiogenesis at 1mM concentrations4. Together, these results demonstrate the potential of using novel flavone derivatives as lead compounds in drug discovery programmes for cancer.References1. C. Holohan et al., Nature Reviews Cancer, 2013, 13, 714-7262. H.M.I. Osborn et al., Int. J. Biochem. Cell Biol., 2013, 45, 2821-2831 3. H.M.I. Osborn et al., RSC Advances, 2016, 6, 64544-64556 4. H.M.I. Osborn et al., Eur. J. Med. Chem., 2015, 97, 259-274BiographyDr. Helen Osborn is currently Professor of Biomedicinal Chemistry at the School of Pharmacy, University of Reading, UK. She undertook her undergraduate studies in Chemistry at the University of Oxford (1987-1991), and her PhD in synthetic chemistry at the University of Bristol (1991-1994). She then undertook postdoctoral research in carbohydrate and natural product chemistry with Professor Steve Ley at the University of Cambridge (1994-1996). In 1996 she was appointed as a lecturer in Biological Chemistry at the University of Reading. Her research focuses on medicinal chemistry programmes relating to cancer and bacterial infections, and has resulted in over 70 research outputs.



Improving the Performance of (Q)SAR Models for Predicting Toxicity Using a SAR Fingerprint MethodologyGlenn J. Myatt*, David Bower, Kevin Cross, Catrin Hasselgren and Donald P. QuigleyLeadscope Inc., USAAbstract

This presentation will outline how knowledge derived from public and proprietary databases can be used to improve different computational models for predicting potential toxicity. This methodology, term SAR fingerprinting, uses thousands of pre-defined substructure searches that systematically explore structural variations around existing structural alerts for toxicity. This list of substructure searches is run over each public and proprietary database and information is shared on the number of positive and negative examples matching each substructure. The results from each participating organization are combined and used to identify structural features that appear to activate or deactivate toxicity, providing a detailed picture of the SAR. This process is guided by both an assessment of whether the proportion of positive examples matching the substructure is significantly higher or lower than expected alongside any mechanistic knowledge to support a theory of activation or deactivation. This methodology has been used to improve the performance of public bacterial mutagenicity expert alerts and QSAR models, without revealing individual confidential compounds or study results. This methodology was run against over 35,000 compounds with bacterial mutagenicity data. The results have been used to improve the overall performance of the expert alerts system and QSAR models for bacterial mutagenicity as well as continued improvements to specific classes including aromatic amines, aromatic amides, aryl boronic acids, and alkyl halides. This presentation describes the benefits of such analysis and details how this analysis can be used to support the prioritization of lead chemicals.Biography

Dr. Glenn Myatt is one of the founders and is currently the Chief Scientific Officer of Leadscope, Inc. He has over 25 years of experience researching and developing in silico solutions. He is currently the principal investigator on two US National Institutes of Health research grants and has co-authored 21 publications, three books as well as five book chapters.

Recent Advances in Design of Hydroxy (aza) naphthalene-carboxamide as AntimicrobialsJosef Jampilek1*, Tomas Gonec2, Jiri Kos1,2 and Sarka Prochazkova2

1Comenius University, Slovakia2University of Veterinary and Pharmaceutical Sciences, Czech RepublicAbstract

Infectious diseases represent an increasing worldwide threat. Development of resistance to used drugs and development of cross-resistant or multidrug-resistant strains are a global problem. In addition, the number of infections that can be associated with specific species as well as the number of new species as etiological agents has exploded in the last few years due to the increase in the number of immunocompromised patients. The presence of an amide group with a hydrophobic residue in its close vicinity is characteristic of a number of biologically active compounds. The amide is an important functional group that is able, due to its electron properties, to interact and bind with a number of enzymes/receptors and by means of these target sites affect the biological response. Therefore, the reason for widespread occurrence of amides in modern pharmaceuticals and biologically active compounds is obvious. The properties of the amide moiety can be easily modified by various substitutions. Thus the presence of an amide-like moiety is characteristic for various antibacterial, antimycobacterial or antiparasitic agents. Hydroxynaphthalene- or (di)azanaphthalene-based carboxamides have a broad spectrum of antimicrobial activity. These simple scaffolds possess unique physico-chemical properties and provide a possibility of a great number of targeted modifications. This contribution is focused on new potential antimicrobial agents, the structure of which contains an amide moiety as an essential fragment causing a significant activity.This study was supported by the Slovak Research and Development Agency (Grant No. APVV-0516-12). This contribution utilizes also research results of the CEBV project (ITMS 26240120034).Biography

Dr. Josef Jampilek completed his Ph.D. degree in Medicinal Chemistry at the Faculty of Pharmacy of the Charles University (Czech Republic) in 2004. In 2004-2011 he worked in expert and managerial posts in the R&D Division of the pharmaceutical company Zentiva. In 2009 he became an Associate Professor of Medicinal Chemistry at the Faculty of Pharmacy of the University of Veterinary and Pharmaceutical Sciences. Now he is at the professor position as a Head of the Department of Pharmaceutical Chemistry of the Faculty of Pharmacy, Comenius University (Slovakia). He is an author/co-author of 29 patents, more than 140 peer-reviewed scientific publications, 15 chapters in monographs and many invited lectures. He received several awards for his scientific results.



Evaluation of Parenteral Nutrition Nanoemulsions as a Drug Delivery SystemMohammad Najlah1* and Abdelbary Elhissi2

1Anglia Ruskin University, UK2Qatar University, QatarAbstract

Lipid nanoemulsions have been increasingly used as carriers for poorly soluble drugs owing to their biocompatibility and biodegradability [1, 2]. We have investigated commercially available Total Parenteral Nutrition (TPN) nanoemulsions, namely Intralipid 20% (Fresenius Kabi, Germany) and Clinoleic 20% (Baxter Healthcare, USA) nanoemulsions as vehicles and solubilizers of drugs that have been known of their poor solubility, permeability and/or stability. The stability of the drug-loaded Intralipid® and Clinoleic® nanoemulsions were evaluated over 90 days at room temperature and at 4°C. Size analysis, zeta potential and pH measurements were performed periodically. Full evaluation of the delivery system such as entrapment efficiency, release study ...etc. was reported for each drug using suitable and validated methods. For the blank and freshly loaded emulsions, the droplet size was highly dependent on nanoemulsion type. The polydispersity (PDI) was generally higher for the Intralipid emulsion. Zeta potential values were negative for both emulsions. the drug concentrations had no impact on the droplet size and PDI for both emulsions. However, pH of Intralipid emulsions increased because of drug loading but no similar effect was reported for Clinoleic emulsions. After 14 days, the pH of both emulsions significantly decreased upon storage at room temperature. Therefore, both emulsions are not stable when stored at room temperature for more than 14 days. Both emulsions showed high stability after 60 days of storage at 4 °C. In vitro biological evaluations confirmed the high feasibility of using TNP as drug delivery system for problematic drugs such as paclitaxel, ciprofloxacin or disulfiram. [1] M. Najlah, M., Kadam, A., Wan, K., Ahmed, W., Taylor, K. and Elhissi, A. Int. J Pharm, 506(1-2), (2016), 102-109.[2] A. Kadam, M. Najlah, K-W. Wan, W. Ahmed, S. Crean, D.A. Phoenix, K.M.G. Taylor, A. Elhissi, Pharm Dev. Tech, 19, (2014), 999-1004. Biography

Mohammad is a multidisciplinary Pharmaceutical Scientist with excellent experience of Pharmaceutical Higher Education as a teacher, researcher and strategic senior manager. He is currently Deputy Head of Department for Medicine and Healthcare science at Anglia Ruskin University (ARU).Since joining ARU, Mohammad has been instrumental in developing the SuperLabs Complex, High-Tech teaching and research facilities and the establishment of new undergraduate and postgraduate programmes. Mohammad’s research interests focus on the fabrication of multifunctional nanomedicines for drug delivery application, developing nano-formulations for respiratory drug delivery, the effect of formulation on the performance of medical devices and clinical Pharmaceutics.

Anti-inflammatory and Wound-healing Activity of Euphorbia characias subsp. wulfenii and Bioassay-guided Isolation of Quercetin-3-O-galactosideSerkan Özbilgin1*, Özlem Bahadır Acıkara1, İpek Süntar2, EsraKüpeli Akkol2 and Gülçin Saltan1

1Ankara University, Turkey2Gazi University, TurkeyAbstract

Euphorbia is the largest genus in the Euphorbiaceae family, which contains at least 2000 species. Euphorbia species, containing diterpenoids, flavonoids, volatile compounds and tannins, are known to have cytotoxic, antitumor, antibacterial, anti-inflammatory and anti-HIV activity, and some of them are used in folk medicine to treat skin diseases and wounds. In this study, five species have been selected from Euphrobia genus, of which some species are used traditionally as wound healer in Turkey, and bioactivity-guided fractionation method has been used to isolate the active compounds.

In line with this purpose, wound healing and anti-inflammatory effects of n-hexane, ethyl acetate, and methanol extracts, which were successively prepared from aerial parts of E. macroclada, E. seguieriana subsp. seguieriana, E. characias subsp. wulfenii, E. virgata and E. helioscopia species were tested. For wound healing activity assay, linear incision and circular excision wound models were used. For antiinflammatory activity assay, an acute inflammation model, namely acetic acid induced capillary permeability increase inhibition method (Whittle method) was used E. characias subsp. wulfenii methanol extract which has the highest wound healing activity among extracts prepared, were separated into its fractions by column chromatography for isolation of efficient compounds. Biological activity of the fractions was assessed and further isolation and purification processes have been carried out in the active fraction.

Chemical structure of the isolated compound was determined by various spectroscopic methods. The isolated compound from active fraction was detected as quercetin-3-O-galactoside (hyperoside).Biography

Dr. Serkan Özbilgin is a pharmacist research assistant at Pharmacognosy department in Ankara University, Faculty of Pharmacy in Turkey. He was born in Antalya on 1 February 1983 and graduated from Ankara University, Faculty of Pharmacy in 2006. He has remained at the university to complete his master of sciences degree and PhD, in Pharmacognosy. He is a member of Pharmacognosy and Phytotherapy Society, Ankara Pharmacists Society in Turkey.


Phyto-chemistry: An Old Concept for Solving Modern Drug ProblemsBassem A. SabryNational Research Centre, EgyptAbstract

Pharmaceutical agents (mostly known as drugs) are one of the greatest discoveries and inventions in the modern era that was the answer for several catastrophic diseases and saved and still saving millions of lives every place of the planet.

Although there are undeniable benefits of pharmaceutical drugs there comes another important inseparable term which is called side effects that vary from rare to common and from mild to severe and Adverse drug reaction (ADR), then comes the problem of the balance sheet (pros versus cons) their also comes other problems like patient compliance and another special problem which we will focus on which is the Anti-Infective Agents that most recently was the reason of developing resistant vicious microorganism strains that represent the new challenge for this era.

These problems increased the interest for safer source of treatment with high efficacy and lower side effects and that was by returning back to nature and to herbal remedies and that was manifested in its most obvious form in chicken flu where the solution was in developing Tamiflu from star anise.

Star anise as an example was quite intriguing so I investigated it more thoroughly and the results indicated that the major components of star anise essential oil identified by GC/MS were trans-anethole (82.7%), carryophyllene (4.8%) and limonene (2.3%). Total phenolics of ethanol and methanol extracts recorded 112.4 and 96.3 mg GAE/g DW respectively, whereas higher total flavonoid content was recorded for the ethanol extract than the methanol extract. Star anise essential oil showed lower antioxidant activity (55.6 mg/mL) than the extracts using DPPH-scavenging and b-carotene/linoleic acid assays. Results indicated high antifungal activity on Aspergillus flavus, Aspergillus parasiticus and Fusarium verticillioides as growth reduction when using 100 ppm concentration of essential oil by 83.2%, 72.8% and 65.11%, respectively, where a complete inhibition was achieved at 200 ppm for A. flavus and A. parasiticus, respectively.



Fibrate-Based Analogues as PPARs Agonists: Synthesis and Structure–Activity RelationshipsLetizia Giampietro1*, Antonio Laghezza2, Alessandra Ammazzalorso1, Barbara De Filippis1, Marialuigia Fantacuzzi1, Cristina Maccallini1, Fulvio Loiodice2 and Rosa Amoroso1

1G. d’Annunzio University, Italy2Aldo Moro University, ItalyAbstract

Peroxisome Proliferator-Activated Receptors (PPARs) are nuclear hormone receptors expressed in metabolically active tissues.Three isoformswere identified to date, namely PPARα, PPARγ and PPARδ, are important in lipid metabolism and glucose homeostasis. Dual PPARα/γ agonists, which stimulate both PPARα and PPARγ isoforms, are able to reduce side effects of selective PPARα or PPARγ agonists and may be used for dyslipidemia and type 2 diabetes mellitus simultaneously.1Fibrate analogues active as PPARagonists have, as typical pharmacophore, a carboxylic acid head and an aromatic ring with or withoutvarious spacers. In the past, we reported different fibrate analogues with good activation of PPARs.2-4In particular, one of the best compounds was the dual PPARα/γ agonist GL479, with (E)-1-phenyl-2-[4-(2-phenylethoxy)phenyl]diazene as aromatictail (αEC50=0.6 µM and γEC50=1.4 µM).5 This molecule was crystallized with the PPARα and PPARγ to better understand the interactions with the receptors.GL479 complexed with PPARa and PPARg occupies the ligand-binding pocket of PPARa (red) and PPARg (gray) in two distinct conformations (Figure 1).6

Figure 1.A) Figure 1.A) General structure of fibrate analogues; B) PPARα/γ agonist GL479; C)Overlap of GL479 with PPARα and PPARγ.After these promising results, and in order to gain more insight on the structure-activity relationships, we synthesized new GL479 analogues with different substituents in para to the phenyldiazenyl moiety and with the oxygen of the linker in para to the 2-methyl-2-phenoxypropanoic group. All compounds were testedon PPARs and the results showed that some of these are promising candidates to develop new morepotent and selective fibrate analogues active on PPARs.1. Gao, Q. et al. Bioorg. Med. Chem.2015, 23, 7676–7684; 2. Giampietro, L.et al. J. Med. Chem.2009, 52, 6224–6232; 3. Giampietro, L. et al. Med. Chem.2014, 10, 59-65; 4. Giampietro, L. et al. Chem. Biol. Drug. Des.2016, 87, 467–471; 5. Giampietro, L. et al. Bioorg. Med. Chem. Lett.2012, 22, 7662–7666; 6. dos Santos, J. C. et al. J. Struct. Biol.2015, 191, 332–340.Biography: Dr. Letizia Giampietro has completed Degree in Pharmacy (2000)and received her PhD in Medicinal Chemistry (2003) fromthe University “G. d’Annunzio” of Chieti (Italy).From 2006 to date, she is Assistant Professor of Pharmaceutical Analysis. Her research interests include medicinal chemistry and are above all focused towards the synthesis of fibrate derivatives active on Peroxisome Proliferator-Activate Receptors (PPARs). Lately, her research isdirect toanticancer, neuroprotective and antioxidant agents. .

Anti-mycobacterial Activity of Novel D-/L-alaninyl 5-(1H-1,2,3-triazolyl) Methyl OxazolidinonesOludotun A. Phillips*, Leyla H. Sharaf, Vidhya Thomas and Roselyn J. D’SilvaKuwait University, KuwaitAbstract

Tuberculosis (TB) caused by Mycobacterium tuberculosis (M. tb) accounted for 10.4m cases in 2015 with an estimated 480000 new cases of multidrug-resistant TB. Drug resistance continues to be a growing health issue hence the urgent need for development of new anti-TB agents. Oxazolidinones are active against both Gram-positive bacteria and M. tb. D-/L-alaninyl 5-triazolylmethyl oxazolidinones were synthesized according to reported synthetic methods and evaluated against M. tb H37Rv in BACTEC 12B medium-Microplate Alamar Blue Assay. Cytotoxicity was determined by measuring THP-1 human monocytic cell line viability after 3 days in the presence of test compounds using the cell titer-Glo luminescent cell viability assay (Promega) which uses ATP as an indicator of cell viability. Initially, 15 compounds were screened by measurement of growth in liquid medium of a fluorescent reporter strain of H37Rv, using a Biotek Synergy 4 plate reader. Rifampicin and metronidazole were used as controls for aerobic and anaerobic killing of M. tb, respectively. Seven most active compounds were subjected to further in vitro activity characterization. Time-kill assay was used to measure bactericidal activity. MIC and MBC were measured under aerobic and low oxygen conditions against resistant strains of M. tb. D- and L-alaninyl oxazolidinones showed MIC ranges of 0.39-22 and 0.69-19 µM against M. tb H37Rv, and 0.042-29 and 0.24-33 µM against resistant strains, respectively. The seven compounds were bactericidal (MBC: 0.17-25 µM) with MIC ranges of 0.24-10 and 0.22-5.8 µM under low and normal oxygen conditions. Three derivatives (PH-224(D), -232(L) and -214(D)), were potent against intracellular M. tb, IC50: 0.50, 1.2 and 3.5 µM, respectively. D-alaninyl PH224(D) and L-alaninyl PH232(L) derivatives containing 5-nitrothiophene carbonyl group, were two most active and noted to be cytotoxic. No significant differences in activity were noted between the D- and L-isomers. Kuwait University, Research Sector Grants GS 01/01, GS 01/03 & GS 01/05 (SAF) and National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) Contract no. HHSN2722011000091 / HHSN27200004 A 19.Biography

Prof. Oludotun A. Phillips received his PhD from the University of Saskatchewan, Canada, and postdoctoral studies from the University of Alberta, Canada. He acquired Pharmaceutical Industrial Experience at Synphar Laboratories, Edmonton, Canada, as a Research Scientist and rose to the rank of Project Manager. He later joined the Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University as an Associate Professor in 1999. He is currently a Professor of Pharmaceutical & Medicinal Chemistry at Kuwait University. He has published more than 70 peer reviewed papers in reputed journals and co-authored 8 patents.



The Effect of Kaqun Water on the Functions of Elderly PeopleIvan SzalkaiKaqun Europe cPlc. Hungary Abstract

Kaqun water is produced by a special method. This water contains 130-170% oxygen and free radicals. This water is rapidly absorbed, the rising of subcutaneous oxygen level can be measured only 5 minutes after consumption. The transport is not realized by hemoglobin way. Hypothetical mechanisms reduce the tissue’s hpoxia and free radicals related effects. The applicability of Kaqun water is under investigation in several areas currently. In the present work we have studied the effect of this water on cardio-vascular and mental functions of elderly people in a randomized, double-blind, control group. We have examined the plethysmogram, the standard deviation of the pulse in relaxed state and under stress with the tools of HRV analysis, the speed of vasodilation (flexibility), blood pressure (systolic and diastolic), oxygen saturation, SRT (reaction time) and CRT (cognitive time). We have experienced significant changes in the reduction of systolic blood pressure, reflex time, cognitive time and stress index.Biography

Dr Ivan Szalkai is a medical researcher in the research group of Kaqun cPlc. He researches the effect of Kaqun water on the immune system and HIF level, and examines the uses of Kaqun water in emergency situations and in preventive geriatrics. He manages the Ayurveda laboratory in the University of Debrecen, Hungary. In the University of Miskolc, Hungary, he manages the Ayurveda education. He is co-chair of Hungarien Scientific Ayurveda Society. He has written a book about the results of Kaqun’s research, which was published in Hungarian and English. He regularly gives lectures on the effects of Kaqun water.

Design Conception, Synthesis, Leishmanicidal Activity and Druglikeness Profile of New Amide Mimetic DerivativesLídia Moreira Lima*, Marina Amaral Alves, Aline Cavalcanti de Queiroz, Barbra Moraes, Sandra Elisa Haas, Magna Suzana Alexandre Moreira and Eliezer J. BarreiroUniversidade Federal do Rio de Janeiro, Brazil Abstract

Considering the ability of proteases to catalyze the hydrolysis of peptide bonds, compounds containing amide or amide-mimetic frameworks can be designed as proteolytic inhibitors and be studied as antitrypanosomatid candidates. In this abstract, we describe the design conception, synthesis, leishmanicidal activity, drug likeness profile and ADME study of new hydra zide-N-acylhydrazone derivatives, containing a new peptide mimetic framework. These derivatives were synthetized in linear four steps process, were characterized and their purity determined by HPLC and elemental analysis. The in vitro leishmanicidal activity against amastigote forms of L. amazonensis and L. braziliensis were determined, highlighting compounds LASSBio-1705 e LASSBio-1707 e LASSBio-1736. These compounds were evaluated in vivo, in a model of cutaneous leishmaniasis (dose = 30 µmol/kg/day during 28 days), in BALB/c mice infected with L. amazonensis. The aqueous solubility, chemical and plasma stability of LASSBio-1705 e LASSBio-1707 e LASSBio-1736 were determined. All compounds were very stable at pH =7.4, but only LASSBio-1736 remained stable at pH=2.0. In rat plasma these compounds showed great stability. The Pharmacokinetic profile of LASSBio-1736 in rats by oral (12.6 mg/kg) or i.p. (12.6 mg/kg) administration was determined. In summary we described the discovery of new leishmanicidal lead-candidate (i.e. LASSBio-1736), with high stability in plasma and in pH conditions that mimic gastric and plasma environments. This compound, bearing a new peptide mimetic framework, has great metabolic stability in rats, with half-life of ~28h, and total clearance of ~50mL/Kg/h. However, it showed low oral bioavailability that can be, in part, due its low aqueous solubility (0.85 µM). BiographyDr Lídia Moreira Lima is Associate Professor in the Biomedical Institute of Sciences from Federal University of Rio de Janeiro. She received her MSc (1997) and her DSc degree (2001) in Medicinal Chemistry from Chemistry Institute of Federal University of Rio de Janeiro. She conducted post-doctoral research at the Department of Pharmaceutical Chemistry at the University of Navarra, Spain (2004-2005). Her main scientific interests involve the molecular design, synthesis, metabolism study and lead-optimization of new drug candidates for cancer, diabetes and neglected diseases.



Solubility of Celecoxib in 2-Propanol + Water Mixtures at Various Temperatures: Experimental Data and Thermodynamic AnalysisSara Nozohouri and Abolghasem Jouyban

Tabriz University of Medical Sciences, Iran

Abstract Due to low aqueous solubility of most of drugs, solubilization of drugs is a mainly discussed, but still not absolutely resolved concern in pharmaceutical area. Cosolvency, a traditional solubilization method, is one of the most applied techniques because of its simplicity and cost effectiveness. The objective of the present investigation is to study the effect of a cosolvent (2-propanol), on the solubility of celecoxib at different temperatures. In shake-flask method, for being sure about the saturation of prepared solutions, the samples are typically prepared by adding an excess amount of drug to the solution mediums, which are different solvent mixtures composition of 2-propanol+water. Samples were placed on a shaker-incubator. A period of 48hr was needed for solutions to achieve equilibrium at the deliberated temperature. Then, they were filtered and aliquots were analyzed at 254.5 nm by UV-spectrophotometer and the molar concentrations were calculated using the calibration curve. The obtained data were correlated/predicted by cosolvency and thermodynamic models. The solubility of celecoxib is increased with the addition of 2-propanol to the aqueous solutions and increased temperature leads to enhance the solubility of celecoxib in a given solvent composition and reaches a maximum value in neat 2-propanol.The results show that 2-propanol is an adequate solubilizing agent for celecoxib. The developed cosolvency and thermodynamic models i.e. Jouyban-Acree and van’t Hoff models are capable to predict the solubility of celecoxib in different fractions of 2-propanol+water solvent mixtures at various temperatures.Keywords: Celecoxib, solubility profiles, solubility, solvent mixture, mathematical model

BiographySara Nozohouri has completed MSc in Pharmacy from Tabriz University of

Medical Sciences, Iran with G.P.A 77%. Currently she is working on drug solubility and its prediction using computational methods. Her fields of interest are broad such as: Drug Development and Discovery, Application of chemo metric approaches and modeling in pharmaceutical sciences, Pharmaceutical and biomedical analysis of drugs. She got recently employed in one of well-known companies in my field, “ZAHRAVI Pharmaceutical company” which is under the license of F.Hoffmann-La Roche, Swiss. She also work part time in pharmacies to stay updated.

Herbal drugs in Algeria: Regulation and RegistrationAmel BouzabataUniversity of Badji-Mokhtar, AlgeriaAbstract The World Health Organization (WHO) encouraged developing countries to integrate into their health system, herbal remedies ensuring safety, efficiency and quality aspects are guaranteed. Algeria has a reserve of herbal drugs, knowledge and expertise in traditional medicine for human and veterinary use. The objective of this work is to present national drug regulation of herbal medicines and the introduction of measures for the alleviation of the marketing authorization procedure. For this, we summarize the regulatory environment for herbal medicinal products (HMP) in Algeria, as well as the most marketed HMP; and present the legislative criteria to improve the marketing authorization procedure for herbal drugs. These measures have been proposed on the basis of comparative law between the European and Algerian regulations. In addition, a list of herbal drugs with a serious risk for the health was specified as recommended by the European Medicine Agency (EMA).Keywords: safety, efficiency, quality, Algeria, regulation Herbal drugsBiography

Dr Amel Bouzabata is a research professor in Pharmacognosy, she has instructed since 2007 at the faculty of Medicine, Badji-Mokhtar University, Annaba, Algeria. After obtaining a doctoral fellowship, with the collaboration of the University of Corsica, Dr. Amel Bouzabata conducts his research for the valorization of traditional medicine as well as the study of natural products from Algerian flora. She is the author of two books and more than ten publications. She studied for the first time the Saharan myrtle and has discovered two new molecules. Further research will be conducted for the development of biological activities.



Design, Preparation and Evaluation of EGDMA Cross-Linked Polyvinyl-pyrrolidone / Acrylic Acid Hydrogel for Controlled Delivery of Quetiapine: In-vitro In-vivo ChapterMuhammad AkhlaqGomal University, PakistanAbstractThe study aims to design and formulate Polyvinylpyrrolidone-Acrylic Acid (AA) based hydrogels using dexibuprofen as model drug and to evaluate the impact of monomer, polymer and cross-linker in different concentration on swelling and release behavior of drug over different pH (1.2, 5.5 and 7.4) of the simulated GIT fluid. The series of hydrogel formulation was based on chain formation of PVP/AA and EGDMA as cross linker in the presence of Benzoyl Peroxide as initiator. Prepared hydrogels were investigated for swelling behavior in different pH medium (1.2, 5.5, 6.4, 7.4), sol-gel fraction, porosity, diffusion coefficient (D) and equilibrium water content (EWC). Hydrogels were characterized by using Differential Scanning Calorimetery DSC. Release of dexibuprofen from PVP/AA hydrogels and the swelling behavior was found to be increased positively with change in pH from acidic to basic. Swelling behavior was strengthened by increasing the acrylic acid and decreased by increasing the contents of EGDMA. The drug release behavior was found to be diffusion based the release data was fitted to various kinetic models including Zero Order, First Order, Higuchi and Korsmeyer-Peppas equation. Pharmacokinetics studies using albino rabbits were conducted and various parameters including Cmax, Tmax, AUC0-t and t1/2 were found to be 18.22±0.87ug/ml, 8.02±0.54hrs, 265.57±5.65ug.hrs/ml and 10.22±0.98, respectively, for the selected optimized test hydrogel formulation. The developed hydrogel was found to be pH sensitive and might be used for colon targeted delivery of the model drug. Biography

Dr Muhammad Akhlaq has completed his Ph D in Drug Delivery. Currently he is working as an Assistant professor of Pharmaceutics in Gomal University, Pakistan. His research interests are Oral drug delivery systems, transdermal controlled drug delivery patches, colon targeted and pH sensitive hydrogels, orodispersible films.Current project: Working on designing the patent of transdermal controlled release patches.

Molecular Design of Hydrotropic Graft Polymers for Dissolution of Poorly Soluble CompoundsTooru Ooya* and Motomi KimuraKobe University, JapanAbstract

In last decade, many researchers have tried to increase bioavailability of poorly soluble substrates such as lipophilic vitamins (e.g., vitamin A and E), polyphenols, curcumin, and paclitaxel (PTX) as a solid dispersion-based dosage form. However, this has been still concerned due to insufficient dissolution rate in aqueous media. Solubility of the poorly soluble substrates is believed to be associated with the amorphous state of the drugs in the solid dispersion. However, the relation between the molecular structure and the solubility is still not clear. We have focused on hydrotropic polymers as a new candidate of water-soluble polymers for enhanced solubility (M. Kimura, T. Ooya, J. Drug Deliv. Sci. Tech;, 2016, 35, 30-33) and solid dispersion. Hydrotropic polymers that are synthesized by polymerization of monomers containing hydrotropic groups can be used as a hydrophobic building block for constructing solubilizer of poorly water soluble drugs(T. Ooya, S. C. Lee,K. M. Huh, K. Park, in: Nanocarrier Technologies: Frontiers of Nanotherapy, Mozafari, M. Reza, Ed., Springer, Netherlands, 2006, pp.51-73.). In this study, hydrotropic graft polymers bearing hydrotropic property were synthesized and evaluated as novel candidates for the medium of solid dispersion of paclitaxel (PTX). In addition, from the analysis of the dissolution behavior of each solid dispersion, correlation between the molecular structure of the polymer as the medium for the solid dispersion and the physical properties of the solid dispersion was discussed.Biography

Dr. Tooru Ooya is Associate Professor of Graduate School of Engineering at Kobe University, where he has been since 2008. He received B.S. in Food and Nutritional Science from University of Shizuoka, Japan (1993) and his Ph.D. in Materials Science from Japan Advanced Institute of Science and Technology ( JAIST)(1997). He spent 8 years as a Research Assistant Professor at JAIST, then moved to Toyama Prefectural University ( Japan) as Associate Professor in 2006. From 2001 to 2002, he worked at Purdue University (USA) as a Visiting Research Scholar. Selected honors include The Controlled Release Society - Nanosystems Outstanding Pharmaceutical Paper Award (2004).


Cell-free Tissue Engineering Based on Drug Delivery Enhan-cement of Regeneration Matej Buzgo1,2,3, Michala Rampichova1,2,3, Karolina Vocetkova1,2,3, Franco Rustichelli2, Andrea Staffa1,2,3, Vera Lukasova1,2, Eva Filova1,2 and Evzen Amler1,2,3

1Charles University in Prague, Czech Republic 2Academy of Sciences of the Czech Republic, Czech Republic 3Czech Technical University, Czech Republic Abstract

Cell based tissue engineering suffers from wide range of ethical, legal and technical obstacles, which limit clinical use of developed tissue. An alternative approach proposed in present work is based on utilization of scaffolds with embedded drug delivery systems as cell-free systems.

We have successfully developed novel drug releasing scaffolds based on core/shell nanofibers prepared by electro spinning and centrifugal spinning technology. The technology enables long term preservation and release of protein based active molecules. We have utilized the technology for delivery of synthetic growth factors (i.e. TGF-beta, bFGF, IGF-I) and natural growth factors (i.e. platelet rich plasma). Scaffolds enabled long term delivery of active molecules in order of 3-4 weeks with regulation of release half-life by changing of core/shell ratio and cross linking rate. In order to demonstrate feasibility of technology, we have showed bioactivity both in vitro and in vivo. The scaffolds were shown to improve bone and cartilage healing of both small and large animal models. The formed tissue showed homogenous distribution and quality bone tissue formation.

The results of studies demonstrate potential of cell-free scaffolds as a viable alternative of classical route of tissue engineering. Such alternative approach reduces market barriers leading to efficient ATMPs uptake by market and fosters application of tissue-stimulating biopharmaceutical use in clinical practice. Biography

Matej Buzgo, MSc has experience in development of drug delivery systems by electro spinning, centrifugal spinning and electro spraying. His main interest is in preparation of core/shell nanofibers by needleless electro spinning and centrifugal spinning for drug delivery of proteins and small molecules. He is coauthor of >15 scientific publications, >5 national and European patents and leads one European and one nation grant projects.


2June 20

Tuesday

Particle Engineer for Improved Drug Delivery (Micro/Nano-crystals)Ali NokhodchiUniversity of Sussex, UKAbstract

Engineered particles in micro and nano scales can offer many advantages to the formulations over other conventional formulations. These engineered particles can alter the delivery of the drug towards the patient’s benefits. Particle engineering has begun to change the scale and techniques of drug delivery and hold huge potential for future developments, particularly in oral and pulmonary delivery. Moreover, it can potentially reduce the cost of drug discovery, design and development. This presentation covers recent developments in the area of particle engineering for oral delivery of poorly water soluble drugs and pulmonary delivery via dry powder inhalers with an emphasis on the results obtained by the presenter within the last 15 years. The surface design of nanoscale structures for improved drug delivery to the lung will be a part of the presentation. A wide range of pharmaceutical applications of hollow particles, particles with nano surfaces and nanocrystals will be discussed. This is a very important area for the pharmaceutical industry today, as it has been reported that the total market for nanotechnology-enabled drug delivery was valued at $78.54 billion in 2012. This is just the beginning of the growth as it is projected reaching potentially $177 billion by 2019 provided that the production methods of these nanocrystals or microparticles with nanosurfaces are cost effective. Therefore, it is best to adhere to Occam’s razor (the law of parsimony) when intending any new marketable design.Biography

Dr. Ali Nokhodchi is currently a Professor of Pharmaceutics at University of Sussex, UK. He has supervised over 15 PhD students in various fields of pharmaceutics. He is an editorial board of over 20 peer-reviewed international journals. Ali has published over 190 research articles in pharmaceutics. In addition, he published 5 book chapters and has been the editor of a book on pulmonary delivery published by Wiley in 2015. He has been the recipient of several prizes in pharmaceutical sciences and has been listed in the top 1% scientists in the field of pharmacology and toxicology published by Essential Science Indicators.



Spraying Technologies to Facilitate Naproxen DissolutionAmal Ali Elkordy University of Sunderland, UKAbstract

Most of newly developed drugs show poor solubility or are completely insoluble in water. Drugs that exhibit poor water solubility demonstrate an incomplete and erratic absorption which ultimately leads to therapeutic failure. The aim of this study was to improve the dissolution of a model hydrophobic drug (naproxen) through spraying technology in the presence and absence of hydrophilic surfactants. Through spraying, particle size was reduced both in presence and absence of hydrophilic surfactant, poloxamer or oleic acid ester. Particulate formulations were then characterized by in-vitro dissolution and various other tests to determine possible changes in structure and particle characteristics. The reduction in particle size via spraying processes is partly responsible for the increased dissolution of naproxen. The hydrophilic surfactant, poloxamer 407 or oleic acid ester, also contribute towards increased drug dissolution. It can therefore be said that spraying processes are effective tool to enhance dissolution properties of poorly water soluble drugs.Biography

Dr. Amal Ali Elkordy is Reader in Pharmaceutics, School of Pharmacy and Pharmaceutical Sciences, University of Sunderland, UK. Her area of research interest includes stabilisation of protein formulations and their delivery. Her work in this field has been recognised by three awards. Her more recent work is concerned with enhancement of poorly-water soluble drugs using for example spray drying technology, liposomal formulations and liquisolid technology, resulting in the award of three prizes. She also has research interests in gene therapeutics (awarded national recognition from the College of Mental Health Pharmacists, 2010). She has published more than 50 papers in reputable journals.


Electric Field Engineering of Drug Dosage FormsRita Haj AhmadDe Montfort University, UK Abstract

This talk focuses on an evolving technology which has potential impact on healthcare sciences. Electrohydrodynamic atomisation (EHDA) is a single step and multipurposeengineering method which uses electrical fields, instantaneous formulation flow and different formulations to yield advanced structures of biomedical importance. The fundamental principal of EHDA is based on liquid atomisation utilising an electrical force in order to construct micro- and nano- assemblies. These include particle, fibre, bubble and printed constructs. These assemblies have proven to be suitable for drug delivery, targeted drug delivery, tissue engineering, wound dressings, sustained drug delivery and tissue engineering); with possibility to enhance other emerging healthcare fields (e.g. imaging). EHD systems were found to significantly improve; bioavailability of existing active pharmaceutical ingredients (hydrophilic or hydrophobic), encapsulation efficiency, dissolution and stability. This talk will specifically focus on different types of dosage forms and bio-structural developments in our laboratory e.g. ocular, buccal, microneedles and intravenous, giving the audience an introduction of the principal of EHD and the critical process and materials parameters. The presentation will also provide an overview of developments in the field which has generated good interest nationally (EPSRC EHDA Network) and internationally.Biography

Dr. Rita Haj Ahmad obtained her PhD from University of Sunderland (UK) and is currently a postdoctoral researcher at The Leicester School of Pharmacy, De Montfort University (UK). Her research interest is focused on utilising various nanotechnologies (e.g EHDA, spray drying, liposome and niosomes) for the delivery of proteins, peptides, antibacterial and anticancer agents. she has published 14 peer-reviewed papers in internationally recongised journals.


Ring-fused Pyrazoles for Cancer Treatment and Nanomedicine ApplicationsMauro Comes FranchiniUniversity of Bologna, ItalyAbstract

Pyrazole derivatives display a broad spectrum of biological activities and represent an important structural class in pharmaceuticals. In this presentation the 1,3-dipolar cycloaddition (1,3-DC) of 1,3-dipoles with π-electronic-deficient systems will be presented. This reaction has a high synthetic efficiency and high regio-and stereoselectivity, and it as a popular way for the obtainment of pyrazoles when nitrile imines are as used as dipoles. Among dipolarophiles we have studied the 1,3-DC with simple acetylenes, heteroatom-substituted acetylenes and several cyclic α-β-unsaturated systems as lactones, thiolactones and lactams. The final goal of this research is the synthesis of ring-fused pyrazoles with Pharmaceutical activity against cancer, our best example is shown below. One of the most promising applications of nanotechnology is in the field of medicine. Indeed, a whole new field of “nanomedicine” is emerging. Nanomedicine is the application of nanotechnology to medicine, and the exploitation of nanoplatforms for cancer treatment holds great promise due to the possibility of tailoring the synthesis of nano-carriers in order to produce particles with narrow size distributions and cavities where organic molecules (drugs) together with smaller metallic nano-particles suitable for imaging can be incorporated. Our nano-carriers has shown ability to entrap efficaciously our synthetic ring-fused pyrazoles together with a gold-based metallic nanostructures as diagnostic agent. Biological results in vitro on several cancer cells will be presented as well as some in vivo experiments in tumor-bearing mice using nanomedicine’s approach.Biography

Mauro is an Associate Professor at University of Bologna. He is an author of 101 articles in international journals. The first research interest lies in the field of the organic chemistry for nanotechnologies and nanomedicine. The argument of this research is the functionalization with complex organic molecules of the surface of nanop articles: in particular magnetic nanoparticles, silver, doped-metal oxides, magnesium and gold nanoparticles. The entrapment of organic molecules together with the metallic nanostructures of interest into biodegradable polymeric nanoparticles is also a topic. The further bioconjugation of these polymeric nanoparticles with bio-functional molecules (proteins and peptides) gives nano-carriers for biomedical applications against cancer and neurological disorders.


Site-Directed RNA Editing for Restoration of Genetic MutationsToshifumi Tsukahara*, Luyen Thi Vu, Sonali Bahkta and Hitoshi SuzukiJapan Advanced Institute of Science and Technology, JapanAbstract

RNA editing is a post-transcriptional process that produces various distinct functional proteins from a single gene. The molecular mechanism underlying C-to-U or A-to-I RNA editings are substitutional RNA editing and involves the hydrolytic deamination of a cytosine or adenosine. Because RNA editing has the power to reprogram genetic information on the RNA level, it has great potential for application in transcript repair (diseases related to point mutations); if it is possible to manipulate or mimic RNA editing, genetic mutation-related diseases could be treated.

We are trying to alter the coded message of RNA transcripts by photochemical RNA editing to treat genetic diseases. The blue fluorescent protein (BFP) gene generated form site-directed mutagenesis of 199T>C in green fluorescent protein (GFP) gene as a model, we performed site-directed deamination of C to U by reversible photoligation using hairpin-type template oligonucleotides with carboxyvinyldeoxy-uridine, cvU, at the 5’-terminal. The oligodeoxynucleotide (ODN) was annealed to the target site of the mutated gene. The mutated cytidine was cross-linked with the photo responsive ODN by ultra-violet ray, then received heat-treatment. Finally, the cross-linked nucleotide was cleaved by the photospliting operation. In the trial experiment, a synthetic 100nt oligonucleotide corresponding to the BFP sequence was used as a target. We observed significant transition when a 100-mer ODN was used as a target. Then, we tried to genetic restoration experiments using RNAs as targets. We could restore 7% of the mutated C to U, when in-vitro-synthesized-full-length BFP mRNAs were used as targets. Biography

Dr. Toshifumi Tsukahara obtained PhD on biochemistry in 1987, then received postdoctoral training at the National Institute of Neuroscience, Japan and on molecular biology at Cold Spring Harbor Laboratory, USA. He had been working with Dr. Kiichi Arahata, National Institute of Neuroscience, and contributed molecular pathophysiologican studies in muscular diseases. In 2003, he was appointed a professor of the Center for Nanomaterials and Technology, Japan Advanced Institute of Science and Technology, then moved to the School of Materials Science, JAIST. He has been working on the feature of RNAs, especially on alternative splicing and therapeutic approach for genetic disorders.


The PK-Eye: The Need for an Ocular Flow Model for the Development of New TherapiesSahar AwwadUCL School of Pharmacy, UKUK National Institute for Health Research, UKAbstract

Treating many blinding conditions requires that a medicine be in the posterior cavity for a sufficient period of time. Damage to the posterior segment accounts for over 70% of the blind registrations in Europe. Inflammatory, angiogenic and fibrotic processes in the retina cause tissue damage and vision loss. These biological processes are also major contributors to the failure of current treatments for these diseases. As the elderly segment of the population continues to grow, there is an urgent and unmet need to optimise the dose and duration of action of medicines in the posterior segment. The development of new therapeutic proteins is of particular importance since proteins tend to be fast acting, selective and potent. New dosage forms and drug delivery systems (DDSs) are also being developed to augment the treatment chronic blinding conditions and new DDSs are particularly needed for therapeutic proteins.

To prolong the release of a protein, a wide array of novel injectable formulations are being developed and reported in literature. The PK-Eye in vitro model is a two-compartment, aqueous outflow model that has been shown to be particularly useful to estimate human protein PK profiles and to determine protein stability properties. Given the current design of the PK-Eye, there is now an opportunity to establish correlations with in vivo models using different injectable dosage forms. The PK-Eye model is used to evaluate new DDS and formulations that are being developed to prolong the release a protein therapeutic.Biography

Dr. Sahar Awwad is a postdoctoral research scientist in UCL, School of Pharmacy and UCL, Institute of Ophthalmology (London, UK). She recently completed her PhD with two scholarships i.e. the UCL Overseas Research Scholarship (ORS) and NIHR Biomedical Research in Ophthalmology at Moorfields Hospital. She has worked on various projects that have resulted in the development of a new in vitro model of ocular pharmaceutics along with a new strategy for extending the duration of action of therapeutic proteins in the eye. Her projects are widely based on drug delivery, ocular pharmaceutics, PK and biodistribution properties, protein production and modification and extensive knowledge on protein characterisation. Dr. Awwad is a co-founder of Optceutics, a new company utilising the PK-Eye to develop new formulations.


Ocular Inserts Loaded with Chitosan Nanodispersion for Prolo-nged Treatment of Ocular InflammationHanan Refai1,2*, Nadia Morsi1, Dalia Ghorab1 and Hoda Teba2

1Cairo University, Egypt2Misr University for Science and Technology, EgyptAbstract

Mucoadhesive polymeric films incorporated with ketorolac tromethamine loaded nanodispersion aiming the sustained delivery of the drug to the cornea have been developed and characterized for the treatment of postoperative ocular inflammation. Nanodispersions were prepared by ionic gelation method with various concentrations of chitosan and sodium tripolyphosphate. The developed nanodispersions were analyzed for morphology, particle size, dispersion homogeneity, zeta potential, entrapment efficiency and drug release. The in vitro release behavior of all formulations showed a biphasic sustained release. The nanodispersion that showed the smallest particle size and the highest entrapment efficiency was incorporated in optimized HPMC E15 and Eudragit RL100/HPMC K4m films. The physico-mechanical properties of the films were evaluated to select the optimum formulation to study its ex-vivo transcorneal permeation through freshly excised bovine cornea in comparison with the nanodispersion and the marketed eye drops (Acular®). The polymeric ocular film showed greater permeation than aqueous eye drops. Moreover, the ocular film revealed a prolonged anti-inflammatory effect compared to eye drops when applied to inflamed rabbits’ eyes.Biography

Dr. Hanan Refai grew up in Cairo and received her Bachelor’s degree from Faculty of Pharmacy, Cairo University in 1994. She obtained a Diploma in Pharmaceutics (equivalent to Master’s degree) from Faculty of Pharmacy, Martin-Luther University, Halle-Wittenberg, Germany in 1998. After she obtained her Ph.D. degree from Carolo-Wilhelmina University, Braunschweig, Germany in 2001, she joined Cairo University as an Assistant Professor in 2002. Refai was promoted to Associate Professor at Cairo University in 2012. She achieved the award for best scientific research in Pharmaceutics in 2011, Faculty of Pharmacy, Cairo, Egypt.


Improved Anti-Hyperlipidemic Activity of Rosuvastatin Calcium via Lipid Nanoparticles: Pharmacokinetic and Pharmacodynamic EvaluationVeerabrahma KishanKakatiya University, IndiaAbstract

The intent of this investigation was to improve pharmacokinetic (PK) and pharmacodynamic (PD) effects of Rosuvastatin calcium (RC) by solid lipid nanoparticles (SLNs). RC is anti-hyperlipidemic drug with low oral bioavailability (20%) due to first-pass metabolism. Hot homogenization followed by ultrasonication method was used to prepare RC-SLNs with stearic acid, glyceryl behenate and glyceryl trilaurate as lipid matrices, egg lecithin and poloxamer 188 as surfactants. The prepared SLNs were tested for particle size, PDI, zeta potential (ZP), entrapment efficiency (EE), drug content and in vitro release. Further, PK and PD studies were conducted on selected SLNs. No changes in physical stability of the optimized SLN were observed at refrigerated and room temperature for 90 days. SLNs prepared with glyceryl trilaurate having average size of 67.21±1.71nm, PDI of 0.25±0.01, ZP of -28.93±0.84mV with 93.51±0.34% EE was considered as optimized. DSC and XRD studies revealed that no interaction occurred between the drug and lipid. SEM and TEM studies revealed that SLNs were nearly spherical in shape. PK studies showed improvement in the oral bioavailability (extent of absorption) of SLNs by 4.6-fold when compared to that of suspension. PD study of SLNs in hyperlipidemic rats exhibited a decrease in lipid profile for 36h, while a suspension exhibited for 24h.Biography

Dr. Veerabrahma Kishan, Professor of Pharmacy, graduated from Kakatiya University, post graduation from Andhra University and Dr.rer.nat.(Ph.D) from Friedrich-Alexander University, Germany. He received three gold medals during his graduation. He has 33 years of teaching and research experience. He served as Principal, Chairman, Board of Studies and Dean, Faculty of Pharmaceutical Sciences in K.U. He visited Germany under DAAD fellowships in 1987-1990, 1996, 2002, 2006 and 2009. He got 9 project grants from DAAD, UGC, AICTE and APCOST. He published more than 60 papers and guided 12 Ph.Ds and 84 M.Pharm dissertations. His research interests include drug delivery, drug targeting and isolation of antibiotics from actinomycetes.


Effects of Far-Infrared Onnetsu Therapy on Rheumatoid Arthritis and CancerKazuko TatsumuraGaia Holistic Health Center, USAAbstract

Onnetsu means comfortable heat. The handheld Onnetsuki invented by Dr. Kazuko Tatsumura emits from a special ceramic emitter:

1) Precise 8-14 micron of vibration of the Sun, 2) various degrees of heat.When Onnetsuki is slid over the skin, healthy areas are comfortable, but

IF deep tissue is cold, unhealthy or degenerated, “hot spot” is detected by the temperature sensation reported from the patient. The Onnetsuki is both a diagnostic and therapeutic tool. When this hot spot is effectively treated with Far-Infrared Onnetsu therapy, the hot sensation subsides and the clinical conditions improve. These abnormal “hot spot” coincides with BORT as a negative spot.

The Onnetsu Therapy is based on four historical and scientific facts.1) NASA’s finding regarding Far-Infrared vibration from Sun light2) Traditional Japanese Concept of the significance of Body Temperature3) Theory of Immunology by Dr. Toru Abo, balancing autonomic nervous

system to improve condition of white cells; Immunity4) Promoting four flows of Energy through acupuncture technique

References• Your Immune Revolution by Dr. Toru Abo, Kokoro Publishing • Overcoming Cancer and Other Diseases in a Holistic Way by Tomeko Mitsui & Dr. Kazuko TatsumuraHillyer, Kokoro PublishingBiography

Dr. Kazuko has taught Onnetsu Therapy to MDs and health practitioners over the past decade. Some countries (Peru, Cuba, Mexico) are practicing it in the hospitals and clinics. Clinical Trials have shown improvements on asthma, cancer, diabetes, rheumatoid arthritis, tuberculosis and various painful conditions. Clinical studies from Cuba and Peru will be presented.


Ubiquinone and Ubiquinole Effects on Nitric oxide - Related Dilation of the Rat AortaOleg. Medvedev*, Larisa Kozaeva, Evgeniya Gorodetskaya and Elena I. KalenikovaLomonosov Moscow State University, RussiaAbstract

This study examined whether coenzyme Q10 can improve NO-dependent vasodilatation in the rat aorta after pre-incubation or intravenous administration. In initial experiments, intact isolated aortic rings were incubated with CoQ10 or L-arginine. In further experiments, CoQ10 was administered intravenously in anesthetized rats, then in 2 h aorta was isolated. In both cases, after preliminary preparation the isolated aortic rings were tested for ACh-induced NO-dependent relaxation. ACh elicited a concentration-dependent relaxation of phenylephrine precontracted aortic rings. Relaxant responses to ACh were markedly potentiated after pre-incubation with CoQ10 or L-arginine. The maximum relaxant responses (%) were significantly increased from 64.1±5.3 (control) to 89.8±3.0 and 83.6±3.0 (CoQ10 and L-arg, respectively). The pD2 (-lgEC50) value in control study was 5.81±0.28, after pretreatment with CoQ10 or L-arg were 7.59±0.16 and 7.26±0.32, respectively. There was no difference between CoQ10 and L-arginine groups. After intravenous administration, the relaxant responses to ACh were significantly increased in CoQ10-treated group (94.2±2.0) compared with controls (68.1±4.4). pD2 values were also different between control and treatment groups (5.79±0.29 vs. 8.14±0.65, respectively). Thus, CoQ10 improved NO-mediated vasodilation in rat aorta as well as substrate for eNOS - L-arginine. Our data show that exogenous intravenously administered CoQ10 is able to improve rapidly NO-dependent vasodilation in rat aorta, likely due to accumulation of CoQ10 in the vessel wall. Improvement of endothelial function can contribute, at least in part, to beneficial effects of CoQ10 in cardiovascular diseases associated with endothelial dysfunction.

The study was supported by RSF grant #14-15-00126

BiographyProfessor Oleg Medvedev graduated from the 1-st Pavlov Medical Institute

in Leningrad, 1970. He defended his PhD degree in pharmacology in 1972 and became full professor in 1990. The fields of his interests pharmacology of the cardiovascular system, models of cardiovascular diseases, antioxidants, congestive heart failure, telemedicine and monitoring of health. He is an author of 214 scientific papers published in Russian and international journals (MedLine search 26.01.2017). Since 1992 he is the head of the Department of Pharmacology at the School of Medicine, Moscow State University. He was the supervisor of 31 PhD students.


Pharmacological Characterization of the Dual GPR17 ReceptorMichela Buccioni*, Diego Dal Ben, Catia Lambertucci, Gabriella Marucci, Andrea Spinaci and Rosaria VolpiniUniversity of Camerino, ItalyAbstract

The GPR17 receptor is a G protein-coupled receptor (GPCR) that seems to respond to two unrelated families of endogenous ligands: nucleotide sugars (UDP, UDP-galactose, and UDP-glucose) and cysteinyl leukotrienes (LTD4, LTC4, and LTE4), with significant affinity at micromolar and nanomolar concentrations, respectively [1]. GPR17 is mainly expressed in the CNS and, in general, in organs that can typically undergo ischemic damage. It is well known that this receptor is involved in the differentiation of neuronal cells, the myelination process, and repair mechanisms following a brain insult. GPR17 has been proposed as a potential pharmacological target for the treatment of multiple sclerosis and traumatic brain injury in humans.

In order to pharmacologically characterize the dual profile of GPR17, a new compound designed and synthesized to be able to interact with both the binding sites present in the receptor was tested in comparison with known agonists and antagonists. The experiments were performed using the GloSensor™ cAMP assay that allows monitoring GPCR activity through change in the intracellular cAMP concentration (Figure 1).

Figure 1. Overview of the GloSensorTM cAMP assay: Conformational change upon binding to cAMP that produces an increase of light output

Human embryonic kidney (HEK293) L9-2 cells, stable transfected with the biosensor and transiently with human GPR17 receptor, were used to detect the activity of compounds under study [2]. Results obtained with the new ligand co-incubated with reference antagonists, montelukast and PF4, showed that the designed compound is really able to interact with both sites expressed in the receptor, so behaving as a dual ligand of GPR17.References[1] P Ciana; M Fumagalli; ML Trincavelli; C Verderio; P Rosa; D Lecca; S Ferrario; C

Parravicini; V Capra; P Gelosa; U Guerrini; S Belcredito; M Cimino; L Sironi; E Tremoli; G.E Rovati; C Martini; MP Abbracchio, EMBO J. 25 (2006): 4615–4627.

[2] M Buccioni; G Marucci; D Dal Ben; D Giacobbe; C Lambertucci; L. Soverchia; A Thomas; R Volpini; G Cristalli, Purinergic Signal. 7 (2011): 463-468.

BiographyDr. Michela Buccioni has completed Degree in Pharmacy at University of

Camerino in 1998. And she has completed Ph. D in 2003. She was a Research fellow in the National Institute for Medical Research, Mill Hill, London in 2005. She has received 2007-2009 Post-doc scholarship from University of Camerino. From 2009 to date she is working as Temporary researcher at School of Pharmacy, University of Camerino. In 2016, she was promoted to Associate Professor. She has published 63 scientific papers in international journals and she has presented 109 scientific contributes to international and national symposia. She is the member of Medicinal Chemistry Divisions of Italian Chemical Society and member of the Italian Purine Club. She is referee for many international journals.


Approach to Acupuncture Application to Back-Shu, Front-Mu and Huatuojiaji PointsMehmet Tuğrul CabıoğluMedical School of Başkent University, TurkeyAbstract

Acupuncture, a method of traditional Chinese medicine that uses Back-Shu, Front-Mu and Huatuo-Jiaji points, is especially effective for treating diseases of the visceral organs. I will speak about acupuncture applications for Back-Shu, Front-Mu and Huatuojiaji Points. I want to build a bridge between traditional acupuncture and present-day medicine.

Acupuncture application is based on the fact that Back-Shu, Front-Mu and Huatuo-Jiaji points stimulate related segmental autonomic nerves. Back-Shu, Front-Mu and Huatuo-Jiaji points, is especially effective for treating diseases of the visceral organs. Applying acupuncture on these points affects visceral organs, related meridian and local area. Acupuncture’s effects can be explained as viscero-cutaneous, cutaneo-visceral, cutaneo muscular, and viscero-muscular reflexes. For example, it dilates the bronchus, stomach and intestinal motility, urinary bladder contractions and so on.

Segmental dispersion of the sympathetic and parasympathetic systems is related to the location of Back-Shu, Front-Mu and Huatuo-Jiaji points.

When these points have been palpated, if the person feels tenderness at the point, we think to indicate that there is a problem in point related to internal organs and area of dermatome. When any of the visceral organs malfunctions, positive reactions such as sensitivity or tenderness will be manifested at the corresponding this point. Palpation of sensitive points can be a useful aid to diagnosis.

Stimulating techniques such as acupuncture, moxibustion, or massage maybe applied to these points to relieve disorder of the corresponding organ. Changes in visceral organs caused by application of acupuncture can be explained as modulation of the sympathetic and parasympathetic systems. Biography

Associate Professor Dr. Mehmet Tuğrul Cabıoğlu is the founder and head of “Acupuncture Treatment Unit” at Medical Faculty of Başkent University in Ankara. He has studied about subjects of electro acupuncture, electroencephalograph together with acupuncture application, acupuncture applications in the disease of pain symptom, acupuncture applications in the obesite. In world, first time, acupuncture in Preterm Babies was applied by Mehmet Tuğrul Cabıoğlu and his team. He is the second president of Ankara Acupuncture and Complementary Medicine Association. He has written thirty five papers.


Application of In Situ Intestinal Perfusion Method to Determine Intestinal Permeability Selma SahinHacettepe University, TurkeyAbstract

The gastrointestinal system plays an important role for the absorption of orally administered drugs. The absorption through the intestinal membrane occurs mainly by transcellular and paracellular routes. Transcellular absorption takes places across the epithelial cell membranes and paracellular absorption through the tight junctions between the epithelial cells. Numerous chemical compounds can be used to enhance the transcellular/paracellular transports (and hence absorption) of compounds with low oral bioavailability.

Various methods can be used to determine the intestinal permeability of compounds. According to FDA, these methods include in-vivo intestinal perfusion studies in humans; in-vivo or in-situ intestinal perfusion studies using suitable animal models; in-vitro permeation studies using excised human or animal intestinal tissues; or in-vitro permeation studies across a monolayer of cultured epithelial cells. The in situ intestinal perfusion is a widely used method for the estimation of permeability because it a simple and reliable method for prediction of in-vivo oral absorption in human. In this presentation, this method will be discussed in more detail, and the result of our studies using this method to investigate intestinal permeability in the absence and presence of various chemical compounds (e.g. efflux transporter inhibitors, permeability enhancers), and also in different experimental disease states (e.g. cirrhosis) in rats will be reviewed.

Part of this study was supported by The Scientific and Technological Research Council of Turkey (TUBITAK) [grant number111S335].

BiographyDr. Selma Sahin is a professor of pharmaceutics at Hacettepe University

Faculty of Pharmacy. She received her B.S. (Pharmacy), and M.Sc. (Pharmaceutical technology) degrees from Hacettepe University-Turkey. She received her Ph.D. degree (1996) in Pharmacokinetics from the School of Pharmacy and Pharmaceutical Sciences, University of Manchester-UK. She was a visiting assistant professor at the Faculty of Pharmacy, University of Uppsala-Sweden (1999). She was a Visiting Scientist at the Department of Biopharmaceutical Sciences, University of California San Francisco (2005-2007). Her research interests include pharmacokinetic modelling and simulations, experimental diabetes and cirrhosis, intestinal and liver perfusion studies, uptake/transport studies across various cell lines, bioavailability/bioequivalence.


Brain GDH: Role on Seizures Mechanism and its Modulation as a Tool for Controlling ThemLourdes A. Vega Rasgado1*, Guillermo Ceballos Reyes2 and Fernando Vega Díaz1

1Escuela Nacional de Ciencias Biológicas-IPN, Mexico2Escuela Superior de Medicina-IPN, MéxicoAbstract

Glutamate (GLU) is a major excitatory neurotransmitter and it is known to be the biosynthetic precursor of γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter.GLU participates in intracellular signaling and several pathologies such as epilepsy. Considering that Glutamate dehydrogenase (GDH, E.C. 1.4.1.3.) is a key enzyme for GLU biosynthesis and modulation and an indirect GABA source, the role of GDH on seizure mechanism was investigated by studying the effect of different anticonvulsant, convulsant and antiepileptic drugs on brain GDH activity. Since GLU is a glucogenic molecule and anoxia is a primary cause of convultions, the effect of these drugs on oxygen consumption was also investigated, in order to establish the repercussions of changes in GDH activity on oxygen consumption. All experiments were performed in vitro as well as ex vivo for both oxidative deamination of GLU and reductive amination of α-ketoglutarate (αk).

In vitro, anticonvulsant drugs caused different effects on GDH activity but also on oxygen consumption. Convulsant drugs decreased GLU oxidative deamination and oxygen consumption when αk reductive amination was catalyzed. Antiepileptic drugs decreased decreased GDH activity as well as oxygen consumption.

Ex vivo, anticonvulsants and antiepileptic drugs increased GDH activity but decreased oxygen consumption during GLU oxidative deamination. In contrast, convulsant drugs increased reductive amination of αk and oxygen consumption with this substrate.

These results suggest that GDH represents an important regulation point of neuronal excitability, and modulation of its activity represents a potential target for metabolic treatment of epilepsy and for the development of new antiepileptic drugs.Biography

Dr. Lourdes A. Vega Rasgado was born in Mexico City, Mexico. She was graduated as chemist, bacteriologist and parasitologist at Escuela Nacional de CienciasBiológicas(ENCB) of Instituto Politécnico Nacional (IPN) México, and Master’s degree on pharmacology at Escuela Superior de Medicina of IPN. She has completed Masters degree and PHD on neurosciences at Universidad de Salamanca, Spain.

She is the Professor of general and clinical biochemistry; head of clinical biochemistry academy and of neurochemistry laboratory at biochemistry department from ENCB of IPN. Author of papers in different journals of neuro-biochemistry and neuro-pharmacology.

Main research lines: Alterations of brain biochemistry associated with epilepsy, schizophrenia, Parkinsons and Alzheimers disease; new drugs and diagnostic methods design.


Preclinical Insights on the Effects of Oleoylethanolamide as Novel Potential Pharmacological Treatment for Obesity and Eating Disorders Silvana Gaetani1*, Adele Romano1, Cristina Anna Gallelli1, Justyna Barbara Koczwara1, Tommaso Cassano2, Maria Vittoria Micioni di Bonaventura3 and Carlo Cifani3

1Sapienza University of Rome, Italy2University of Foggia, Italy3University of Camerino, ItalyAbstract

Eating disorders and obesity are disorders of complex etiology with a high morbidity and a high mortality. Current treatments lack sufficient efficacy and are complicated by high relapse rates and a wide range of side effects, thus highlighting the need to identify novel pharmacological targets for more effective and safer therapies. To this aim, we have been focusing on the role played by oleoylethanolamide (OEA).

OEA is generated in the intestine, activates peroxisome proliferator-activated receptor-alpha to regulate fat metabolism and at the brain level recruits different neuronal pathways (1) (oxytocinergic, noradrenergic, and histaminergic neurons) to exert ahypophagic action (2-4). OEA endogenous signaling in the intestine and the brain is altered in animals ad libitum exposed to a fat-enriched diet, thus suggesting that OEA might be part of those mechanisms deregulated by the exposure to an obesogenic condition (5).

Chronically administered OEA is effective in reducing food intake and body weight gain in obese animals. Moreover, our recent findings demonstrated positive effects of OEA in restoring a normal feeding behavior in a model of binge eating, in which female rats with a history of intermittent food restriction show binge-like palatable food consumption after 15 min exposure to the sight of the palatable food (frustration stress).Overall, these preclinical findings support the hypothesis that OEA might represent a novel potential pharmacological target for the treatment of obesity and eating disorders.1. Romano A, et al. Frontiers in Pharmacology. 2015, 6:1372. Gaetani S, et al. Journal of Neuroscience 2010, 30(24):8096-1013. Romano A et al. American Journal of Physiology-Endocrinology And Metabolism. 2013,305(10):E1266-734. Provensi G, et al. PNAS 2014, 111(31):11527-325. Micioni Di Bonaventura MV, et al. Journal of Neuroscience 2014, 34:11316-24


Effects of Intrathecal Administration of Everolimusin a Triple Transgenic Mouse Model of Alzheimer’s DiseaseTommaso Cassano1*, Silvio Calcagnini2, Adele Romano2, Silvana Gaetani2 and Diego Dolcetta3

1University of Foggia, Italy2University of Rome, Italy3The Regina Elena National Cancer Institute, ItalyAbstract

Overwhelming evidence shows a primary role for the mammalian target of rapamycin (mTOR) signalling in the pathogenesis of Alzheimer’s disease (AD).

To investigate the relation between Aβ and mTOR, we injected the synthetic analogue of rapamycin, everolimus, into the cerebroventricular space of a triple transgenic mouse model of AD (3×Tg-AD), which develops age-dependent amyloid-β peptide (Aβ) and tau accumulation associated with cognitive decline. In particular, 6-month-old 3×Tg-AD mice and age-matched wild-type littermates (Non-Tg) were used. At this age, the 3×Tg-AD mice show early intraneuronalAβ accumulation and tau mislocalization, which correlate with the onset of cognitive decline. The mTOR enzymatic activity and the levels of phosphorylatedp70S6K, a downstream target of mTOR, was significantly increased in the 3×Tg-AD mice compared to control mice; centrally administered everolimus significantly reduced the phosphorylation of p70S6K and decreased the levels of APP and Aβ. The Aβ reduction was confirmed by immunohistochemical analysis.

We next sought to investigate the effect of everolimus on the learning and memory of 3×Tg-AD mice, using three independent behavioral paradigms: the novel object recognition test, a behavioral task mainly dependent on multiple cortical areas, the inhibitory avoidance, which is highly dependent on the hippocampus and amygdala, and the spatial version of the Morris water maze, a hippocampal-dependent task. Overall, our data indicate that everolimus infusion rescued the early learning and memory deficits in the 3×Tg-AD mice.

In conclusion, we show that autophagy induction via everolimus may represent a valid therapeutic strategy in AD when administered early in the disease progression.Biography

Dr. Tommaso Cassano has completed MS in Medicinal Chemistry (1999), Ph.D. in Pharmacology and Experimental Therapeutics (2003) from the University of Bari. Research Fellow at Dept. of Cognitive and Molecular Neuroscience, Babraham Institute, Cambridge, U.K. (2000 – 2003), Postdoctoral Fellow, Dept. of Neurobiology and Behaviour, University of California, Irvine, USA (2003), Visiting Researcher at Dept. of Psychiatry and Human Behaviour, University of California, Irvine, USA (2004). He has since 2003 been working at the University of Foggia: Assistant Professor (2003 – 2015), Associate Professor (since 2015) in the Medical School. His main research interest has been the neurochemistry of aging, the developmental neurotoxicology and the pharmacological modulation of neurotransmitter systems.


The Inhibitory Effect of L-cysteine/H2S Pathway on Contractile Response Through RhoA/Rho-kinase in Mouse Corpus Caver-nosumFatma Aydinoglu*, Elif Adibelli and Nuran OgulenerÇukurova University, TurkeyAbstract

The aim of this study was to investigate the possible role of RhoA/Rho-kinase pathway on the inhibitory effect of L-cysteine/H2S on contractile response in mouse CC. Firstly, the cumulative concentration-response curves tophenylephrine (α1 receptor agonist; 10-8-10-4 M) were obtained in isolated mouse corpus cavernosum tissues. Then, the effects of L-cysteine (endogenous H2S substrate; 10-2 M) and sodium hydrogen sulfide (exogenous H2S; 10-3 M) were studied on the contractile response of phenylephrine. The influence of D,L- propargylglycine (PAG, 10–2 M) and aminooxyacetic acid (AOAA, 10–3 M), cystathionine-gamma-lyase (CSE) and cystathionine-β-synthaseinhibitors (CBS) enzyme inhibitors, respectively, were investigated on the contractile response to phenylephrine in the absence and presence of L-cysteine. Furthermore, to examine the involvement of RhoA/Rho-kinase pathway in L-cysteine-induced inhibition, the effect of Y-27632 (10-6 M), a specific Rho-kinase inhibitor, on phenylephrine-induced contractions were studied in the presence and absence of L-cysteine. Additionally, the influence of PAG and AOAA were examined on the phenylephrine-induced contractile responses in the presence of L-cysteine and Y-27632 combination. The phenylephrine-induced contractile responses were significantly reduced by L-cysteine and exogenous H2S.This inhibitory effect of L-cysteine was partially reversed by the pretreatment with PAG and AOAA.Y-27632 almost abolished phenylephrine-induced contractions in the presence of L-cysteine and exogenous H2S. The inhibitory effect of L-cysteine and Y-27632 combination was partially reversed by PAG and AOAA pre-treatment. These results suggest thatthe inhibitory effect of L-cysteine/H2S on contractile response may be through the inhibition of RhoA/Rho-kinase pathway in mouse corpus cavernosum.

Keywords: corpus cavernosum, hydrogen sulfide, mouse, rho-kinaseBiography

Fatma Aydinoglu, PhD is an Assistant Professor at the Faculty of Pharmacy, Cukurova University, Turkey. Her Research areas are Pharmacology, smoothmuscle, nitricoxide, hydrogensulfide, rhoA/rho-kinase. In 2013, she has completed her PhD in Pharmacology, Cukurova University, Turkey.


The Relationship between Awareness Under Conscious Hypnosis (AUCH©) Method and Traditional Chinese Medicine Ali Özden Öztürk* and Gizemnur Öztürk Society of Medical Hypnosis (THD), TurkeyAbstract

Purpose: In this workshop we aim to illustrate the inherent relationship of a conscious hypnosis method named “Awareness Under Conscious Hypnosis (AUCH©)” and Traditional Chinese Medicine (TCM) via live and video applications.

Methods: AUCH© is a state of consciousness created by specific induction techniques and suggestions; and it aims to make changes in attention, perception, memory, emotions and senses of the patient. To create these aimed changes; AUCH© has a treatment protocol consisting of three steps: “1) MAYA© (Making Acceptance with Your Awareness), 2) Induction and 3) Autohypnosis”.

Furthermore AUCH© is an integrative method that can be applied in different fields of medicine. TCM is one of the disciplines that coincide considerably with the hypnotic protocol of AUCH© Method. In other words, the meridians & points used in TCM have a substantial relationship with the various body areas induced spontaneously during the application of AUCH© Method.

Results: The inherent relationship between hypnotic rituals of AUCH© Method and TCM can be illustrated via mapping TCM meridians & points coinciding with the body areas induced spontaneously during the treatment protocol of AUCH© Method.

Conclusions: The mapping showing the corresponding points and areas of AUCH© Method and TCM can illustrate the inherent relationship existing between these two methods in a systematic way.Biography

Dr. Ali Ozden Ozturk is the founder member and current President of Society of Medical Hypnosis (THD), Turkiye; former BOD member of European Society of Hypnosis (ESH); holder of European Certificate of Hypnosis (ECH); and also member of ESH, International Society of Hypnosis (ISH), World Association for Positive Psychotherapy (WAPP), Istanbul Acupuncture and Integrative Medicine Society. As a hypnosis trainer and supervisor, certified acupuncturist, positive psychotherapist and family consultant, he makes interdisciplinary studies to elaborate the mechanism of hypnosis. Besides his studies in universities, he has his private practice with applications of AUCH© (Awareness under Conscious Hypnosis).

Workshop

3June 21

Wednesday

Exploring the Impact of Sample Flow Rate on In vitro Measure-ments of Metered Dose Inhaler PerformanceDA Lewis1*, H O’shea1, TK Church1, G Brambilla1, D Traini2 and PM Young2

1Chiesi Limited, UK2The University of Sydney, AustraliaAbstract

Pharmacopoeial methods for measurement of the aerodynamic particle size distribution (APSD) of metered dose inhalers (MDIs) by cascade impaction specify a sampling flow rate of 28.3 L/min. However, there is little data within the literature to rationalize this figure, or to support its clinical relevance. In addition, the standard United States Pharmacopoeia Induction Port (USP IP) used for testing is known to inaccurately reflect deposition behavior in the upper airway, further compromising the relevance of testing, for product development. This article describes experimental studies of the effect of sampling flow rate on APSD data gathered using an Andersen Cascade Impactor (ACI). Tests were carried out using two different formulations to assess the influence of formulation composition. In addition, comparative testing with an Alberta Idealised Throat, in place of the USP IP, to ensure more realistic representation of the upper airway. The results show how measured APSD and fine particle dose, the dose than on the basis of size would be expected to deposit in the lung, vary as a function of test methodology, providing insight as to how the testing can be modified towards greater clinical relevance.Biography

Dr. David A. Lewis established Chiesi’s UK research centre in 2008. He holds a B.Sc. in Physics (1989) and M.Sc. and Ph.D. in Aerosol Science (1990 & 1994), from Essex University, England. David co-authored over 160 research publications and over 30 pharmaceutical related patents. These inventions led to Chiesi’s Modulite Metered Dose Inhaler technology which has seen formulations of beclomethasone dipropionate, budesonide, formoterol and a beclomethasone dipropionate-formoterol combination commercialized across the world.



Microscale Particle Image Velocimetry to Assess Powder Dis-persion within a Dry Powder InhalerTeresa Carvajal1*, Xiang Kou2, Steven. T. Wereley1, Paul W.S. Heng2 and Lai Wah Chan2

1Purdue University, IN, USA 2National University of Singapore, Singapore Abstract

The dispersion mechanisms of dry powder inhalers are still a challenge. In vitro characterization on fine particle fraction has been the parameter to address. Even though, that is the important aspect for the success of acceptable deposition of particles in the lung, optimization of fine particle fraction requires having a fundamental understanding on the mechanisms of powder dispersion upon actuation of a dry powder inhaler (DPI). Carrier based DPI formulations were prepared for visualization of the aerosolization process. The dry powder aerosolization process was visualized in a transparent model Rotahaler® chamber using a high-speed camera. The aerosolization process was directly observed and analyzed. Powder dispersion mechanisms include drag force, impact with obstacle and particle-particle collision. Particle flow pattern and collision regions were identified using image analysis techniques. This presentation shows the mechanisms that govern powder dispersion from a DPI. The information can help to DPI formulation development and stability with higher performance.Biography

Dr. M. Teresa Carvajal is a faculty member of Agricultural and Biological Engineering (ABE) at Purdue University. Her research focuses on the study of the properties of powders and powder technology, including solid-solid and solid-liquid interactions as strategies for formulation. Prior to joining Purdue, Dr. Carvajal worked in the pharmaceutical industry for 13 years. Her work include on the properties and behavior of powders and powder blends extended into the development of powder-device combinations for pulmonary delivery of peptides and small organic molecules. Her research interests are on the physico-chemical properties of powders, surface properties (interactions and composition) and their implications on performance.


Theoretical Mass Spectrometry of Testosterone and AnaloguesKihyung Song1*, Giae Lee1, Eunkyung Park1, Heesun Chung1, Wooyoung Shim1, Jihye Yang1, Hyeran Song1, Seunghee Cho1 and Riccardo Spezia2

1Korea National University of Education, South Korea2CNRS, FranceAbstract

Theoretical mass spectrometry of testosterone was calculated using QM + MM direct dynamics simulations. Intermolecular potential was set as exp-9 Buckingham equation with parameters fitted to ab initio calculations. The intramolecular potential of testosterone-H+ and its gradient, which is necessary to solve classical mechanical equation of motion, was obtained from a quantum chemistry program, MSINDO. VENUS, a classical trajectory calculation program, was used to solve the equation of motion of the nuclei of the system. This calculation gave us the coordinates of nuclei as a function of time. By visualizing and analyzing the animation of the motion of nuclei, it was possible to determine the structures and formation of pathways of all ionic as well as neutral products, especially m/z 97, 109, and 123 peaks on which there are several experimental suggestions. The theoretically determined mechanisms and structures of those ions were well-agreed with experimental ones. The analogues of testosterone such as boldenone, which has one more double bond on the first six-membered ring, had been studied using simpler QM method, PM3. Hence this method could be used as a supplemental method for determination of product structures and formation pathways of the peaks of mass spectrums.Biography

Dr. Kihyung Song, born 1958, graduated from Seoul National University in 1981, and has completed his PhD at the age of 31 from Texas Tech University. Since then, he has been a Professor of Department of Chemistry at Korea National University of Education. He is the chairman of the department now. He has published more than 100 papers on theoretical and computational chemistry in reputed journals.


Cost And Health Benefits From Integrating New Age Ayurveda Into European Health SystemsHarsha Gramminger Euroved GmbH, GermanyAbstractGeneral Health Costs are spiraling in all developed and developing nations of the world. In 2013, Germany spent almost € 315 billion on health. This was an increase of about € 12,1 billion compared to 2012 : 3910,00 € in 2013 vs. 3770,00 € in 2012 per inhabitant. Type 2 Diabetes, Obesity, Hyperlipidemia, Hypertension & Other “civilization” diseases are the main factors for these costs. With over 8 million sufferers (in 2009 and growing), Diabetes Mellitus is one of the most widespread diseases in Germany. Serious “secondary complications” and “associated diseases” / co-morbidities include heart attack, stroke, athlete’s foot etc. Total costs € 3.817.00 includes three components: Direct - disease, Indirect& associated complication. Obesity is another new global epidemic and set to become the “number one health problem globally” by the year 2025. In 2013 52% of all Germans were overweight, which is about 42.02 Million people! The associated conditions include: Type 2 Diabetes, Hypertension, Vascular diseases, Stroke, Coronary heart disease, Gall stones, Cancer, Sleep Apnea Syndrome, Diseases of the joints and of the skin and more. Clinical and practical experience is proven, that Ayurveda is able to improve the condition of both Type 2 diabetes and Obesity. Furthermore it is able by its lifestyle guidance and preventive holistic approach, to reduce and avoid follow – up diseases and costs. The presentation will show with facts and figures how the wisdom of Ayurveda can be followed for the New Age to prevent, manage and cure such diseases. Figures for savings to the European Health care costs will be presented and discussed.Biography

Dr. Harsha Gramminger is the Managing Director of Euroved – Ayurveda Made in Europe. The Ayurveda doctor is responsible for the Euroved Clinic and especially for Panchakarma retreats as well as for the education of Ayurvedic doctors and therapists. She has distilled the foundations of New Age Ayurveda in a trilogy of German-language books: Meine Basics, Mein Handbuch and Mein Kochbuch. She also works as the president of the European Ayurveda Association (EUAA).


The Self Medications Use among Adolescents aged between 13-18 years old; Prevalence and Behavior, Riyadh-Kingdom of Saudi Arabia for the Year 2014-2015Shahd AlAwwad*, Turki Albatti, Roqaih Aldueb, Razan Alhoqail and Rawan AlmutairiKing Saud University, Saudi ArabiaAbstract

Background and objectives: In Saudi Arabia, people have easy access to medication and can purchase prescribed medications, such as anti-acne medications and antibiotics, over the counter without the need for a prescription from a physician.

Our research is focused on estimating the prevalence of self-medication and understanding the reason for self-medication because previous studies have shown an increase in the practice of self-medication globally and locally.

The aim of this study is to estimate the prevalence of self-medication among adolescents aged 13-18 years of both genders in Saudi Arabia e Riyadh. In addition, we aim to identify the indications and external and internal factors behind self-medication, including the effects of gender, peer influence and parental supervision on the decision of adolescents to self-medicate.

Methods: An observational and cross-sectional adolescent-based study was performed to estimate the degree of self-medication among 400 intermediate and high school students in private and governmental schools living in Riyadh between 2014 and 2015 using a multistage random sampling technique. A validated self-administered questionnaire was used for data collection, and data were tabulated and analyzed with the SPSS version 21 computer program.

Results: We found that the rate of self-medication among adolescents was high (94.5%). Analgesics were the most common medication used (87.3%), and the least common medication used was hormones (5%). A majority of the students reported that headache was the reason for using analgesics. The sources of the medications included the pharmacy (51.64%), followed by parents (34.33%). The results showed that self-medication was significantly associated with the type of school that the adolescents attended (P < 0.011) and the health status of the adolescents (P -value <0.035).

Conclusion: Self-medication use is highly prevalent in Riyadh, particularly among adolescents, high accessibility to the pharmacies found to be the most leading cause to self-medicate. Using these drugs suggested inappropriate drug use and deterioration of health status. This should be closely monitored and increase awareness with educational programs among students.

Keywords: Self-medication, Adolescents, Riyadh-Saudi Arabia, Prevalence, Behavior


Multimodal Bio-psychosocial Pain Management and Acupunc-ture Toward a New Model in Clinical Practice

Agnès Mazic de SonisPain Clinic Chirec, BelgiumAbstract

The last decennia a multimodal bio-psychosocial management of pain has been proposed. For patients with chronic pain and/or chronic pain refractory to conservative treatment it is important to assess all factors involved with chronicity.

Most guidelines emphasize that pharmacological therapy for persistent pain is most effective when combined with non-pharmacological approaches Nondrug treatments.

The need for a multidisciplinary evaluation and treatment with a focus on the drug metabolism is highlighted. Genetic variations may modulate the answer to treatment as does the inter-individual differences in the bacterial flora of the human digestive tract.

The improved biological, genetic and epigenetic knowledge has contributed to a better understanding of the mechanism of acupuncture. Neuroimaging demonstrate the brain regions activated by acupuncture and also illustrates the differences with sham or placebo. These brain areas are associated with a pain matrix.

In the field of acupuncture research there is a need for a bidirectional approach to acupuncture research, where basic science studies and clinical trials each inform the other. We highlight, the diagnostic steps, that addresses the chronicity and the modified parameters such as sleep, nutrition, reactive depression and the different vicious circles induced by chronic pain (peripheral and central sensitization).

A strategy that integrate neutraceuticals nutrition and acupuncture approach close to analgesics shows as described in literature a better response and tolerance of the treatment, a dose reduction and a significant improvement of the parameters involved in the chronification.Biography

A Mazic de Sonis, PhD, is specialized in pain medicine since 30 years. First trained in France, after a specialization in gynaecology and obstetrics, the interest in the bio psychosocial management of chronic disease and pain treatment allowed a multidisciplinary training involving TCM acupuncture pharma co-nutritional and pain medicine.

In 1990 a pain clinic project has been created in CHIREC Brussels involving all processes in pain treatment and integrative approach. A clinical research on refractory pain treatment, drug tolerance or side effect, efficacy close to acupuncture has been performed since. In the field of acupuncture research there is a need for a bidirectional approach, where basic science studies and clinical trials each inform the other.

She is involved as pain medicine professor and acupuncture in Brussels and Paris in charge of a special interest group integrative pain medicine supported by Belgian pain society (IASP) the project is evaluation and systematisation in a translational way.

Study of Silver or Gold Nanoparticles Interactions with Skin Layers by Vibrational SpectroscopyAdela Jenistova*, Marcela Dendisova and Pavel MatejkaUniversity of Chemistry and Technology, Czech RepublicAbstract

The healing effects of silver and gold nanoparticles (AgNPs, AuNPs) are already known from ancient times. Moreover, considering their antibacterial and anti-inflammatory effects speculations are being discussed with respect to these nanoparticles (NPs) about their effect on the enhancement of skin penetration properties. In this study the interactions of pig skin (PS) layers and ointments with different amounts of added AgNPs or AuNPs prepared by standard chemical procedures and also by “green” synthesis were studied by infrared (IR) and Raman spectroscopy. Vibrational spectra of untreated PS and PS treated by pure ointment were measured, as well as PS samples healed by ointment modified with vitamins without addition of NPs or with different proportions of NPs. Kinetics of interactions of modified ointments with PS were monitored during two hours in the five-minute intervals between each two consecutive measurements. The obtained series of spectra were evaluated by exploratory Principal Component Analysis (PCA), Partial Least Squares (PLS) regression and Soft Independent Modelling of Class Analogy (SIMCA) classification which revealed observation of spectral changes in time-dependent spectra and variations of the peak intensity ratios. The study showed that the effects of quantity and type of NPs on skin penetration characteristics are evident and significant. The results obtained will be further supplemented by near-field IR microspectroscopy and confocal Raman microspectroscopy.Biography

Dr. Adela Jenistova studied doctoral program at University of Chemistry and Technology Prague with an aim of using of vibrational spectroscopy for skin analysis.



Salmoncalcitonin Modulates Calcitonin Gene-related Peptide Levels in Peripheral Blood by Stabilizing Mast Cells in the Dura- Mater in RatsErkan Kilinc1*, Yasar Dagistan1, Aysel Kukner1, Bayram Yilmaz2, Sami Agus2 and FatmaTore3

1AbantIzzet Baysal University, Turkey2YeditepeUniversity, Turkey3Biruni University, TurkeyAbstract

Mast cells (MCs) play key role in migraine pathophysiology. CGRP is established as migraine biomarker in peripheral blood. Salmon-calcitonin has anti-nociceptive and anti-inflammatory effects. We aimed to investigate effects of mast cell degranulation and salmon-calcitonin on CGRP levels and dural mast cell behaviours in rats.

Forty-nine male wistar rats (150-180g) were used. Groups including control (n=7) vehicle (0.2ml, i.p.); C-48/80 (n=7) compound-48/80 (MC degranulating agent, 2mg/kg, i.p.); Cromolyn+C-48/80 (n=7) sodium cromoglycate (MCstabilizing agent, 50mg/kg, i.p.) and C-48/80 together; Calcitonin+C-48/80 (n=7), salmon-calcitonin (50µg/kg, i.p.) and C-48/80 together; DGMC(n=7) degranulated peritoneal MCs (0.2ml, i.p.); Calcitonin+DGMC (n=7), salmon-calcitonin (50µg/kg, i.p.) and degranulated peritoneal MCs (0.2 ml). In meningeal preparations, hemiskulls (n=7) were exposed vehicle or C-48/80 (300µl, 10 µg/ml) for 15min. Plasma and meningeal CGRP levels were measured using enzyme-immunoassays. Dural MCS were stained and examined. Data were analyzed with one-way ANOVA-Tukey using SPSS_17.0.

Both C-48/80 and degranulated peritoneal MCs increased plasma CGRP levels and degranulation of dural MCs, respectively (p<0.001), while C-48/80 didn’t change CGRP levels in meningeal preparations. Cromolyn blocked fully increases in plasma CGRP levels and increases in degranulation of dural MCs induced by C-48/80 (p<0.001). Salmon-calcitonin decreased increases plasma CGRP levels and in degranulation of dural MCs induced by C-48/80 (p<0.05 and p<0.01) respectively. While degranulated peritoneal MCs increased total mast cell number in dura mater (p<0.01), these increases were diminished by salmon-calcitonin (p<0.05).

Our findings suggest that mast cell degranulation contributes neurogenic inflammation underlying migraine by inducing CGRP release, and salmon-calcitonin is able to prevent mast cell degranulation in dura mater and CGRP release. Mast cell stabilizing agents and blockers of CGRP release such as salmon-calcitonin may be new treatment options for migraine.**Study was supported by AIBU, Scientific-Research-Fund [Grant-number: 2016.08.02. 1060].

BiographyDr. Erkan Kilinc is working as assistant professor and head of Department of

Physiology, Faculty of Medicine at Abant Izzet Baysal University, Bolu, Turkey. He carried out his PhD thesis studies on the purinergic mechanisms in migraine pain under leadership of Prof. Rashid Giniatullin in Kuoipo in Finland.

A 4-Week Repeated Dose Oral Toxicity and Effect of Hwangryunhaedok-tang on Human Drug-metabolizing EnzymesSeong Eun Jin*, Hyeun-Kyoo Shin and Hyekyung HaKorea Institute of Oriental Medicine, South KoreaAbstract

Hwangryunhaedok-tang (HHT; Huanglianjiedu-tang, Orengedoku-to) is a traditional herbal formula used for the treatment of inflammatory, gastrointestinal and cardiovascular diseases. The purpose of this study was to evaluate the sub-acute toxicity of HHT in Sprague-Dawley (SD) rats, and its effect on the activities of human microsomal cytochrome P450s (CYP450s) and UDP-glucuronosyl transferases (UGTs). Male and female SD rats were orally administered HHT once daily (0, 500, 1000 and 2000 mg/kg) for 4 weeks. Mortality, clinical observations, body weight, food consumption, organ weights, urinalysis, hematology, serum biochemistry and histopathology were analyzed. The activities of major human CYP450s (CYP1A2, CYP3A4, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP2E1) and UGTs (UGT1A1, UGT1A4 and UGT2B7) were assessed using in vitro fluorescence- and luminescence-based enzyme assays, respectively. The effects of HHT on the activities of CYP450s and UGTs were presented as IC50 values. No toxicologically significant changes related to the repeated administration of HHT were observed in both male and female SD rats. The no observed adverse effect level (NOAEL) was more than 2000 mg/kg/day for both genders. HHT inhibited the activities of CYP1A2, CYP2C19, CYP2D6 and CYP2E1, whereas it weakly inhibited the activities of CYP2B6, CYP2C9, CYP3A4 and UGT1A1 in human microsomes. In addition, HHT negligibly inhibited the activities of human microsomal UGT1A4 and UGT2B7 with IC50 values in excess of 1000 µg/mL. Collectively, our results indicate that HHT may be safe for repeated administration up to 4 weeks. In addition, our findings provide information on the safety and effectiveness of HHT when co-administered with conventional drugs.Biography

Seong Eun Jin is a researcher at K-herb Research Center in Korea Institute of Oriental Medicine. Her research interest is in the area of pharmacological activities of herbal medicine, drug metabolism and herb-drug interactions.

Repeated Dose 28-Day Oral Toxicity Study of Yongdamsagan-Tang, a Traditional Herbal Formula, in Crl:CD Sprague Dawley RatsEunsook Park*, Mee-Young Lee, Chang-Seob Seo,Hyeun-Kyoo Shin and Hyekyung HaKorea Institute of Oriental Medicine, South KoreaAbstract

Yongdamsagan-tang, a traditional herbal formula, is used widely for the treatment of inflammation and viral diseases. However, the safety of Yongdamsagan-tang administration have not yet been established. In this study, we investigated the repeated dose28 day oral toxicity of Yongdamsagan-tang water extract (YSTE) in Crl:CD Sprague Dawley rats (n=5). Rats were treated with YSTE at doses of 0, 1000, 2000 and 5000 mg/kg administered once a day by gavage for 4 weeks. There were no significant changes in mortality, organ weights, food consumption, serum biochemistry, and conducted hematology and urinalysis. In clinical signs, however, salivation and discolored urine in all rats treated with YSTE at 5000 mg/kg/day were observed. In necropsy finding, discoloration in liver of both male (n=1) and female (n=3) rats were observed at 5000 mg/kg/day. In organ weights, the relative weights of kidney and liver in male rats were also found at 5000 mg/kg/day. These results suggest that no-observed-adverse-effect level (NOAEL)of YSTE were seen at 5000 mg/kg/day or less.Biography

Dr. Eunsook Park received the B.Sc., M.Sc. and Ph.D. degrees in School of Biological Sciences and Technology from Chonnam National University in 2004, 2006 and 2012 respectively. In 2014-2015, she joined Gwangju Center, Korea Basic Science Institute, Gwangju, Republic of Korea, as Post-doctoral Research Fellow. Since December 2015, she is a senior researcher at Korea Institute of Oriental Medicine, Daejeon, Republic of Korea. Her current research interest is the study of the therapeutic effect and safety (toxicity) of traditional herbal medicine against various diseases including male urogenital disease (benign prostatic hyperplasia) and immune-related diseases (asthma and chronic obstructive pulmonary disease).

Poster Presentations



The Antibacterial Activity of Honey Against Pseudomonas aeruginosais Enhanced by Royal Jelly and Water Soluble PropolisKlemen Rihar1*, DunjaExel Gregorič2, Malči Božnar3 and Bratko Filipič4

1Chengdujska 4, Slovenia2Glavarjeva 45, Slovenia3Beekeeping »Božnar« d .o.o., Slovenia4HIETO, CroatiaAbstract

Pseudomonas aeruginosa is a cause of burn sepsis, being a problem in hospitals and in elderly homes, due to ineffective antibiotic treatment. Important is its increasing resistance to antibiotics. RJ is yellow emulsion with antibacterial activity against Gram positive and Gram negative bacteria are connected to proteins and 10-HDA. Propolis is a mixture of: flavonoids, minerals and proteins with antibacterial activity against Gram positive bacteria and Gram negative bacteria. Aim of the experiments was to elucidate the enhancing effect of RJ and WSP on the antibacterial activity of Honey against Pseudomonas aeruginosa. RJ was from Beekeeping Božnar. Water-soluble Propolis (WSP) was Greit120 (Italy). Honey was from Beekeeping Rihar-Kocjan. In the combination experiments RJ diluted 1:10 and 1:100 and WSP were mixed in 1:1 and added as 10% to the Honey. The antibacterial activity was expressed as MIC (Minimal inhibitory concentration) (mg/ml). The MIC of Honey (1:10) was 0.062. RJ had MIC: 0.25 (1:10) and 0.5 (1:100). WSP had MIC: 0.031 (1:10) and 0.125 (1:100). When RJ (1:10 and 1:100) was added as 10% to the Honey, the MIC was 0.015. The addition of WSP shows the following MIC: 0.015 (1:10) and 0.007 (1:100). When the RJ (1:10) and WSP (1:10) were added to the Honey, the MIC was 0.031. Addition of RJ (1:100) and WSP (1:100) gave MIC = 0.014. The addition of RJ (1:100) and WSP (1:10) as 10% to the Honey increases the MIC to 0.007. The highest MIC (0.003) was obtained when the RJ was 1:10 and WSP was 1:100. The enhancing activity of RJ or WSP on antibacterial activity of Honey was concentration dependent in a way that the mixture of 1:10 of RJ and 1:100 of WSP as 10% to the Honey show the best MIC (0.003).

Bone Mineral Density is Reduced by Telmisartan in Male Spontaneously Hypertensive Rats Antonio Marcos Birocale1*, Ana Raquel Santos Medeiros1, Leandro Dias Gonçalves Ruffoni2, Liliam Takayama3, José Martins de Oliveira Jr.4, Keico Okino NOnaka1, Rosa Maria Rodrigues Pereira1 and Nazaré Souza Bissoli1

1University of Espirito Santo, Brazil2Federal University of São Carlos, Brazil3University of São Paulo, Brazil4University of Sorocaba, BrazilAbstract

Background: Telmisartan, an angiotensin AT1 receptor blocker, and treadmill running were compared for their effects on bone mineral density (BMD) and biomechanical properties of male spontaneously hypertensive rats (SHR). It was hipothesized that running (18m/min/60min/day) and telmisartan (5mg/kg/day) would have a positive effect on bone parameters.

Methods: Three-month old male SHRs were divided into three groups: sedentary (S), telmisartan (T) and exercise (E). At the end of an 8-week protocol, femur and lumbar vertebrae were analyzed by dual-energy X-ray absorptiometry (DXA) for bone mineral density and by the three-point bending test for biomechanical properties. Blood pressure in all groups was measured by a tail-cuff manometer.

Results: Telmisartan and treadmill running reduced blood pressure when compared to the sedentary group; however, telmisartan did not improve bone characteristics. Instead, it reduced BMD of femur total and lumbar vertebrae and worsened bone biomechanical properties. Treadmill running maintained bone characteristics and hence was effective in maintaining bone health.

Conclusion: Results showed that telmisartan negatively affected bones suggesting that caution should be taken in possible therapeutic applications for protecting bone health in hypertensive conditions. More studies are necessary to clarify the mechanisms through which telmisartan favors bone loss in this model.Biography

Antonio Marcos Birocale has a degree in Physiotherapy from the Federal University of São Carlos (1992) and a master’s degree in Physiological Sciences from the Federal University of São Carlos (1997). Since 2010, he teaches Physiotherapy course at the Federal University of Espirito Santo. He has experience in the area of the Kinesiology and Biomechanical Assessment and Sports Physiotherapy.

Formulation and In vitro Characterization of Porous Silica as Drug Delivery System and Regenerative Device for BoneWiesław Sawicki*, Katarzyna Czarnobaj and Magdalena ProkopowiczMedical University of Gdańsk, PolandAbstract

Silica-based mesoporous oxides are one of the most progressive biomaterials useful in bioactive delivery drug system researches. Their characteristic feature is uniform nanoporous structure which is similar in magnitude to the molecular size of the drugs, ability to form apatite layer and actively bond to the surrounding bone tissue as well as low susceptibility to bacterial colonization, and absolute resistance to corrosion.

The purpose of this study was to evaluate the surface mineralization activity and in vitro drug behavior of mesoporous silica in the form of powder and granulate as potential biomaterials to bone regeneration and as the drug delivery systems.

Ordered mesoporous SiO2 powder was synthesized by surfactant assisted sol-gel process. The produced powder silica was next granulated using ethyl cellulose as a binding agent.

Metronidazole (MT) - an anti-inflammatory substance and doxorubicin hydrochloride (ChD) - an anticancer drug were chosen as drug models for delivery studies.

The results of structural characteristics studies show that obtained materials have two dimensional hexagonal p6mm symmetry, high specific surface area, narrow pore size and a satisfactory mineralization behavior in the simulated body solution (SBF, pH = 7.4).

The release rate of drugs depends upon the form of the carrier material and interactions of the medicinal substance with surface of the carrier. Slowest release was observed for ChD from granulates (46% after 72 h).

In conclusion, the results of this study emphasize the potential of nanoporous silica as dual-drug loaded delivery system in treatment and regeneration ofdiseased hard tissues.Acknowledgements: This project was supported by the National Centre for Science of the Polish State (“OPUS” project: 2012/07/B/NZ7/04385).

BiographyProf. Dr hab. Wiesław Sawicki, Ph.D., D.Sc. Faculty of Pharmacy, Medical University of Gdańsk ( Poland). Head of the

Department of Physical Chemistry. Dean (2008-2016) of the Faculty of Pharmacy, Medical University of Gdańsk. Member of several scientific and professional bodies. Reviewer of ca. 200 manuscripts of publications and research projects- pharmaceutical technology - tablets, pellets, therapeutic systems and physical pharmacy.

Effects of the Endo Cannabinoid System on CGRP Levels of Plasmain Nitroglycerin-Induced Migraine Model in RatsErkan Kilinc* and Yasar DagistanAbantIzzet Baysal University, TurkeyAbstract

Aims: Endo-cannabinoidanandamide is an endogenous ligand for cannabinoid CB1 and CB2 receptors which play a key role in the modulation of pain. In particular, CB1 is able to inhibit pain impulses from A- and C-fibres innervating dura mater. Calcitonin gene-related peptide (CGRP) is postulated as a biomarker of migraine. Therefore, in preliminary study of our project, we investigated effects of (R)-methanandamide (AEA) on CGRP levels of plasmain nitroglycerin-induced migraine model in rats.

Methods: Wistar male rats (130-150 g) were divided into four groups (n=7 for each group). Rats were administered vehicle (control) or nitroglycerin (10 mg/kg, i.p., NTG group). Other rats received AEA (20 mg/kg/i.p.) or vehicle 30 min before NTG administration, AEA+NTG and vehicle+NTG groups, respectively. All rats were sacrificed 2 h later. CGRP contents of plasma were measured using enzyme-immunoassays. Data were analyzed with one-way ANOVA-Tukey using SPSS_17.0 software.

Results: NTG increased significantly CGRP levels of plasma compared to control (p<0.001). On the other hand, AEA reduced significantly increased CGRP levels of plasma induced by NTG (p<0.01).



Conclusion: Our findings suggested that endo-cannabinoid system is able to diminish nitroglycerin-induced migraine pain by modulating CGRP levels of plasma. However, more study is needed to determine which types of cannabinoid receptors that may be responsible for this effect.** This study was supported by Abant Izzet Baysal University, Scientific-Research-Fund[Grant-number: 2016.08.02.1095].

BiographyDr. Erkan Kilinc is working as Assistant Prof. and Head of Department of Physiology, Faculty of Medicine at Abant Izzet

Baysal University, Bolu, Turkey. He carried out his PhD thesis studies on the purinergic mechanisms in migraine pain under leadership of Prof. Rashid Giniatullin in Kuoipo in Finland.

The Self Medications Use among Adolescents aged between 13-18 years old; Prevalence and Behavior, Riyadh-Kingdom of Saudi Arabia for the Year 2014-2015Shahd AlAwwad*, Turki Albatti, Roqaih Aldueb, Razan Alhoqail and Rawan AlmutairiKing Saud University, Saudi ArabiaAbstract

Background and objectives: In Saudi Arabia, people have easy access to medication and can purchase prescribed medications, such as anti-acne medications and antibiotics, over the counter without the need for a prescription from a physician.

Our research is focused on estimating the prevalence of self-medication and understanding the reason for self-medication because previous studies have shown an increase in the practice of self-medication globally and locally.

The aim of this study is to estimate the prevalence of self-medication among adolescents aged 13-18 years of both genders in Saudi Arabia e Riyadh. In addition, we aim to identify the indications and external and internal factors behind self-medication, including the effects of gender, peer influence and parental supervision on the decision of adolescents to self-medicate.

Methods: An observational and cross-sectional adolescent-based study was performed to estimate the degree of self-medication among 400 intermediate and high school students in private and governmental schools living in Riyadh between 2014 and 2015 using a multistage random sampling technique. A validated self-administered questionnaire was used for data collection, and data were tabulated and analyzed with the SPSS version 21 computer program.

Results: We found that the rate of self-medication among adolescents was high (94.5%). Analgesics were the most common medication used (87.3%), and the least common medication used was hormones (5%). A majority of

the students reported that headache was the reason for using analgesics. The sources of the medications included the pharmacy (51.64%), followed by parents (34.33%). The results showed that self-medication was significantly associated with the type of school that the adolescents attended (P < 0.011) and the health status of the adolescents (P -value <0.035).

Conclusion: Self-medication use is highly prevalent in Riyadh, particularly among adolescents, high accessibility to the pharmacies found to be the most leading cause to self-medicate. Using these drugs suggested inappropriate drug use and deterioration of health status. This should be closely monitored and increase awareness with educational programs among students.

Key words: Self-medication, Adolescents, Riyadh-Saudi Arabia, Prevalence, Behavior.

Protective Effects of Centella asiatica Leaf Extract on the Progression of Non-Alcoholic Fatty Liver DiseaseSe Chan Kang1*, Jeong Eun Kown1, Dae Won Park1, Hae Seong Song1 and Yong Joon Jeong2

1Kyung Hee University, South Korea2Genencell Co. Ltd., South KoreaAbstractLiver diseases are one of the major health problems worldwide. Among them, nonalcoholic fatty liver disease (NAFLD) is (often difficult to treat) a kind of liver disease caused by an accumulation of fat in the liver. Patients with NAFLD have an increased risk to develop liver fibrosis, which leads to cirrhosis. To investigate hepatoprotective effects of Centella asiatica (originated from Jeju Island, South Korea), oleic acid-induced NAFLD in HepG2 cells was used and C. asiatica was fractionated with ethanol (EtOH), n-hexane, dichloromethane (CH2Cl2), ethyl acetate (EtOAc), n-butanol (BuOH), and H2O. Cells treated with the EtOAc fraction showed the highest lipid accumulation inhibiting effect. C. asiatica also suppressed triglyceride accumulation and inhibited expression of lipid marker gene, such as a peroxisome proliferator activated receptors (PPARs) agonist or antagonist. PPARs was significantly increased or decreased by in a dose-dependent manner, respectively. These results suggest that C. asiatica is a potent agent for the treatment of NAFLD. This work was supported by Korea Institute of Planning and Evaluation for technology in Food, Agriculture, Forestry and Fisheries (IPET) through Agri-Bio industry Technology Development Program, funded by Ministry of Agriculture, Food and Rural Affairs (MAFRA).Biography

Dr. Kang is the Director of the Bio-Medical Research Institute and the associate professor of the College of Life Sciences, Kyung Hee University, Korea. He has over 100 peer-reviewed publications studying natural product science and development of health functional food and natural new medicine.

Carob Pulp Purified Extract as Hepato-protective CompoundAdrián Macho-González1*, Alba Garcimartín1, Feras Naes1, M. José González-Muñoz2, M. Elvira López-Oliva1, Sara Bastida1, Francisco J. Sánchez-Muniz1 and Juana Benedí2

1Universidad Complutense de Madrid, Spain2Universidad de Alcalá, SpainAbstract

The present study aimed to evaluate the potential in vivo and in vitro hepatoprotective effect of purified extract of carob pulp (Ex). In vivo experiments were carried out in two groups, control (C) and Ex-treated group (t-Ex) of male 2-months Wistar rats. Diabetes was induced with streptozotocin and nicotinamide (65 and 225 mg/kg b.w., respectively). All rats were fed a hypercholesterolemic diet with 1.4% cholesterol and 0.2% colic acid during 8 weeks, and t-Ex received a dose of 125mg/kg b.w. the last 4-weeks. At the end of the study the animals were sacrificed and hepatosomatic index [liver weight/body weight)*100] was calculated. In vitro studies were conducted in HepG2 cells treated with 200 µM tert-butyl hydroperoxide (t-BHP) to induce oxidative stress, together with two main active metabolites of Ex (3-hydroxyphenylacetic acid (HA) and 3,4-dihydroxycinnamic acid (DC)). Protective effect of both metabolites at 5 µM was tested by a viability study.

Hepatosomatic index was significantly lower in t-Ex rats than in C animals (5.04 ± 0.58 vs. 4.34 ± 0.29; p=0.004), suggesting an improvement of hyperplasia and hypertrophy respect to C group. On the other hand, protective effect of HA and DC metabolites was demonstrated in MTT study showing a significantly increase in cell viability (% respect to control cells) in relation with t-BHP treated cells (59.85 ± 2.62; 59.24 ± 0.40; 55.84 ± 0.49, respectively). In conclusion, HA and DC metabolites seems to be responsible of hepatoprotective effect of Ex.

Supported by AGL2014-53207-C2-2-R (Ministerio de Economía y Competitividad). Pre-doctoral fellowship granted to Adrián Macho-González by FPU15/02759 (FPU, Ministerio de Educación, Cultura y Deporte).



Biological Activity of 2,N6-disubstituted Adenosine Analogues at Adenosine ReceptorsAleix Marti Navia*, Michela Buccioni, Diego Dal Ben, Catia Lambertucci, Gabriella Marucci, Andrea Spinaci and Rosaria VolpiniUniversity of Camerino, ItalyAbstractCrystallographic structures of the A2A adenosine receptor (A2AAR), that presents structural features typical of G protein-coupled receptors, allow acquiring very important information about the interaction of the receptor with the co-crystallized ligands [1]. Results obtained through molecular modeling studies permitted to individuate which amino-acid residues form polar interactions with the 6-amino group of adenosine, and which one binds the aromatic scaffold of the same molecule [2, 3]. Based on these observations, known A2A/A3 ligands modified through the introduction of an N6- amino or N6-alkylamino group were designed and synthesized. These analogues were tested in binding and functional studies at human A1, A2A, A2B, and A3 ARs cloned and transfected in CHO cells. The intracellular cAMP concentration change, after receptor stimulation, was evaluated using the non-radioactive GloSensor cAMP assay. This assay uses a biosensor able to bind the cAMP. The conformational change of the biosensor, due to the binding to cAMP, induces an increase of light output that permits evaluating the activity of ligands at the receptor under study. Binding and functional studies show that the synthesized derivatives are endowed with pronounced affinity and potency at the A3AR subtype and low interaction with the A2AAR. Surprisingly, these compounds behave as A2AAR agonists but show an antagonist profile at the A3AR.

References[1] KA Jacobson, In Silico Pharm 1 (2013): 22.[2] G Lebon; T Warne; PC Edwards; K Bennett; CJ Langmead; AGW Leslie; CG Tate, Nature 474 (2011): 521-525.[3] D Dal Ben; C Lambertucci; G Marucci, R Volpini; G Cristalli, Curr. Top. Med. Chem. 10 (2010): 993-1018.Biography

Aleix Marti Navia has completed Bachelor Degree in “Biochemistry and Molecular Biology specialized in Clinical and Forensic Biochemistry” at Rovira i Virgili University (Spain) in 2014. His thesis in Bachelor’s is about the structural characterization of β2AR C-terminal by NMR. In 2015 he completed Master’s in “Mental Health: Research in Psychiatry, Psychopharmacology and Neurotoxicology” at Rovira i Virgili University, wining the Special Award of Best Academic Record. Master Thesis about the neuro protective effects of leptin and its anti-inflammatories roles. 2016 Course in “Nutrition, Health and Wellness; Food as medicine” at the Open University of Catalonia. Currently studying PhD Course in Chemical and Pharmaceutical Sciences at the University of Camerino (Italy).

Low Level Light Therapy Set and its Selected ApplicationsLukasz Gryko1*, Andrzej Zajac1 and Justyna Szymanska2

1Bialystok University of Technology, Poland2Nicolaus Copernicus University in Torun, PolandAbstract

Low Level Light (Laser or LED) Therapy (LLLT) has been reported to modulate the process of tissue repair by stimulation of cellular reaction such as migration, proliferation, apoptosis and cellular differentiation. Absorbed photon energy enables to induce changes in the biological tissues, and can act as a catalyst for biochemical reactions. The increasing number of papers on LLLT bears witness to the fact that LLLT is interesting and effective healing method although there is still too much skepticism. Nevertheless, today phototherapy LLLT has been well described in many areas of medicine and it has achieved a reliable status worldwide. LLLT is used to: speed up and improve the healing of acute and chronic wounds of various origin, treatment of inflammations and erythemas, accelerate healing of damaged bone, suppression and eradication of acute and chronic pain of various origins, improvement of all aspects of surgery and aesthetic surgery, skin rejuvenation after injury solar, prevent the formation of scars, treatment of circulatory diseases, vascular ulcers and diabetic foot ulcers, and many others applied or still remain in the area of research and testing.

The ambiguities of biological responses result of cells, tissues and organs in consequence of low-power irradiation observed in the available literature were the motivation to elaborate the optoelectronic LLLT set which let to objective evaluation the influence of low power laser or LED radiation in the range of visible and infrared light on the irradiated in vitro tissues. Presented

optoelectronic device allows to controlled and repeatable irradiation of cell lines by low-energy laser or LEDs radiation from the spectral range of tissue transmission window (from 600 nm to 1000 nm). Objective selection and control of exposure parameters allowing comparison of the results for the variable spectral and energetic parameters of radiation. The device also enables the measurement of the sample absorption spectrum during procedure in order to select the appropriate emitter for the medical application.

The set operation had been verificated by carrying out studies on the vascular endothelial cells lines taken from umbilical cord blood – HUVEC. Measurable cellular effects binding a biological response of cells (cell proliferation and growth factor gene expression) with procedure parameters were obtained.Biography

Dr. Lukasz Gryko received his PhD (2015) from the Bialystok University of Technology. He is an associate professor in the Department of Electric Power Engineering, Photonics and Lighting Technology, Bialystok University of Technology. He is involved in the development of optoelectronic systems used in medical applications: Low Level Light Therapy devices and LED’s illuminators for endoscopy.

Simultaneous Quantitation of Ethinylestradiol and Different Progestin’s in Human Plasma by Liquid Chromatography–Tandem Mass Spectrometry (LC-MS/MS) and Application to a Pharmacokinetic Study Pavel Baranov*, Roman Kuznetsov and Svetlana Appolonova I.M. Sechenov First Moscow State Medical University, Russia Abstract

A rapid and sensitive LC–MS/MS method for the simultaneous quantitation of thynilestradiol and different progestin’s (Cyproterone acetate, Drospirenone, Levonorgestrel, Etonogestrel, Dienogest, Gestodene) in human plasma using D3-Ethynilestradiol as internal standard (IS) has been developed and validated. The analytes and IS were extracted from plasma by liquid-liquid extraction with subsequent N,N-dimethylglycin derivatization and separated on a Acquity UPLC BEH C18 (2,1 × 50 mm; 1,7 µm) using a mixture of acetonitrile: 0.05% formic acid (76:24, v/v) at a flow rate of 0.55 mL/min. After electrospray ionization positive ion fragments were detected in the selected reaction monitoring (SRM) mode with a triple quadrupole tandem mass spectrometer. The method was linear in the concentration range of 1.0–200.0 pg/mL or 1.5–500 pg/ml for ethynilestradiol (m/z 381.5->58.1), 0.10-35.0 ng/ml for cyproterone acetate (m/z 417.12->147.1), 0.25-80 ng/mL for drospirenone (m/z 367.2->97.1), 0.1-25 ng/mL for levonorgestrel (m/z 312.2->109.1), 25.0-5000 pg/mL for etonogestrel (metabolite of desogestrel, m/z 325.2->109.1), 2.5-200 ng/mL for dienogest (m/z 312.3->135.4), 0.1-10 ng/mL for gestodene (m/z 326.3->124.0). The intra- and inter-day precisions were below 7.5% and the bias was between -5.3 and +4.8% for all analytes. The method was validated according to FDA guidelines and showed to provide intra- and inter-day precision and accuracy within acceptable limits in a run time of only 3.5 min. The method was successfully applied to a pharmacokinetic study involving a single oral administration of a combination tablets to human women volunteers. This is the first assay method described for the simultaneous determination of Ethynilestradiol and different progestin’s. Biography

Pavel Baranov is graduated from Moscow Medicine Academy and Institute of Pharmacology with the PhD in pharmacology and clinical pharmacology. Since graduating Pavel has held a number of Quality Assurance roles in analytical and bioanalytical laboratories as well as in pharmaceutical and medical devices industries and has acquired over 10 years experience in quality management and auditing.

Pavel’s current role is Quality Assurance Manager in Laboratory of Pharmacokinetics and Metabolomics at the Research Institute of Pharmacy and Translational Medicine (Moscow, Russia) where his responsibilities include ensuring regulatory compliance for non-clinical and clinical studies and risk management activities.



GC-MS and Multivariate Analysis of Siberian Coniferous Trees Pavel Baranov*, Ksenia Shestakova, Roman Kuznetsov and Svetlana Appolonova I.M. Sechenov First Moscow State Medical University, Russia Abstract

Diquertin is an effective antioxidative and capillary protective dietary supplement that contains dihydroquercetine as the active compound. Dihydroquercetine is produced from different parts of coniferous trees (larch, cedar, pine, fir and silver fir). The aim of this study was to compare GC-MS profiles of oil extracts from tissue, root and bark of the coniferous trees utilized in diquertin production. Multivariate analysis the PCA and OPLS were conducted using GC-MS screening in full-scan mode with two different types of sample preparation: using dilute and shoot method with subsequent MSTFA derivatization and without it. Instrumental analysis was performed by single quadrupole mass-spectrometer Agilent 7820 (Agilent Technologies, Waldbronn, Germany) with following preprocessing that included deconvolution, normalization (according to internal standard) and scalling of the received data using free evaluable software AMDIS. After preprocessing, ions were generated in final matrix for subsequent multivariate data analysis that was performed using SIMCA P 14.1 software. The results demonstrated separation of the five groups of trees and presence of specific markers of each type and part of the trees, that could be useful for evaluation of the most suitable material for diquertin production. Biography

Pavel Baranov is graduated from Moscow Medicine Academy and Institute of Pharmacology with the PhD in pharmacology and clinical pharmacology. Since graduating Pavel has held a number of Quality Assurance roles in analytical and bioanalytical laboratories as well as in pharmaceutical and medical devices industries and has acquired over 10 years experience in quality management and auditing.

Pavel’s current role is Quality Assurance Manager in Laboratory of Pharmacokinetics and Metabolomics at the Research Institute of Pharmacy and Translational Medicine (Moscow, Russia) where his responsibilities include ensuring regulatory compliance for non-clinical and clinical studies and risk management activities.

Synthesis and SAR Study of Botryllamides as ABCG2 InhibitorsThomas Willmes and Michael WieseUniversity of Bonn, GermanyAbstract

A common problem in the treatment of cancer is the occurrence of multidrug resistance (MDR). Breast cancer resistance protein (BCRP, ABCG2) is known to efflux several anticancer drugs, among them mitoxantrone and methotrexate, out of cells [1]. In this context, multidrug resistance is associated with the over expression of ABCG2 in cancer cells [2]. One approach is to develop ABCG2 selective inhibitors to overcome MDR. In a high throughput assay a series of botryllamides was identified, able to reverse resistance caused by expression of ABCG2 [3].

Based on the botryllamide scaffold, several derivatives were synthesized. Structural variations of the core structure as well as the substitution pattern were investigated. The biological evaluation was carried out with the Hoechst 33342 accumulation assay. Most of the synthesized inhibitors showed IC50 values lower than 10 µM. Results of the SAR implied that the rigid core structure seemed to be crucial for activity.[1] Doyle, A. L.; Douglas, D. D.; Oncogene 2003, 22, 7340–7358[2] Noguchi, K. et al.; Adv. Drug Delivery Rev. 2009, 61, 26-33[3] Curtis, J. H. et al.; ACS Chem. Biol. 2009, 4, 637-647Biography

Mr. Thomas Willmes was born on 09.05.87 at Arnsberg, Germany. From 2006-2013, he is a research assistant at University of Würzburg. Since 2013, he is a PhD student at University of Bonn, Germany.

Development of Pyrimidine Derivatives as Potent ABCG2 InhibitorsJiyang Li*, Katja Silbermann* and Michael WieseUniversity of Bonn, GermanyAbstract

Multidrug Resistance (MDR) is often a reason for the failure of cancer chemotherapy drugs. The ATP binding cassette (ABC) transporters, including ABCG2, play an important role in the occurrence of MDR, as many of the chemotherapy drugs are substrates of ABC transporters. Pyrimidine was selected as the scaffold for developing ABCG2 inhibitors. Hoechst 33342 and pheophorbide. Assays were used to determine the inhibitory activities on ABCG2. Furthermore, we performed activity screening on ABCB1 and ABCC1 with calcein AM assay. As a result, several compounds were as potent as the standard inhibitor Ko143 in inhibiting ABCG2 and showed no significant inhibition of ABCB1 or ABCC1.Biography

Mr. Jiang Li has studied pharmacy from 2006 – 2010 at the Southwest University in China. Later he studied at Chinese Academy of Medical Science in China from 2010 – 2013. Since 2013, he is a PhD student at Pharmaceutical Institute at University of Bonn.

Ms. Katja Silbermann has studied pharmacy from 2009 – 2013 at the University of Bonn. From 2014 – 2015, she has done M.Sc. in Drug research. In 2015, she was licensed as pharmacist. Since2015, she is a PhD student at Pharmaceutical Institute at University of Bonn.

Investigation of ABC Transporter Inhibition by Modifying the Basic Scaffold of Phenyltetrazolyl-phenylamidesSebastian Köhler*, Sahel Vahdati and Michael WieseUniversity of Bonn, GermanyAbstract

Chemotherapies are often less effective if tumor cells possess a native resistance or become insensitive against a cytostatic drug during therapy. It is supposed that treatment fails in over 90% of patients with metastatic cancer due to multidrug resistance.[1,2]An important mechanism is the increased efflux of cytostatic drugs by the transmembrane ATP binding cassette transporters ABCB1, ABCC1, and ABCG2.

We synthesized derivatives which are structurally related to the ABCB1 inhibitor tariquidar. In previous works, we investigated the influence of the substitution pattern in the outer phenyl rings on the ABCG2 modulation.[6] In the present study, we determined the consequences of altering the basic scaffold on the inhibition potency. The compounds were tested for their inhibitory activities against ABCG2 and ABCB1 by Hoechst 33342 and calcein-AM accumulation assays, respectively. A tetrazol as well as an amide linker are preferred for inhibition. Replacement of phenylring C led to decreased potency.References[1] Longley, D.B.; Johnston, P.G.J. Pathol. 2005, 205, 275-92.[2] Holohan, C. et al.Nat. Rev. Cancer. 2013, 13, 714-26.[3] Szakács, G. et al. Nat. Rev. Drug Discov. 2006, 5, 219-34.[4] Fojo, T. et al. Oncogene. 2003, 22, 7512-23.[5] Köhler, S.C.; Silbermann, K.; Wiese, M. Eur. J. Med. Chem. 2016, 124, 881-95.Biography

Mr. Sebastian Köhler has studied Pharmacy from 2005-2010 at the University of Bonn. Since 2011, he is a Ph.D. student at the University of Bonn.

Mrs. Sahel Vahdati has completed Pharm.D during 2008-2015at Tabriz University of Medical Science, Iran. Since 2016, she is a Ph.D. student at the University of Bonn.



The Interaction of L-cysteine/H2S Pathway and Muscarinic Acetylcholine Receptors (mAChRs) in Mouse Corpus CavernosumFatma Tugce Dalkir1*, Fatma Aydinoglu1*,HaticeOruc Demirbag2 and Nuran Ogulener1

1Cukurova University, Turkey2Mersin University, TurkeyAbstract

The aim of this study was to investigate the possible interaction of L-cysteine/H2S pathway and muscarinic acetylcholine receptors (mAChRs) in the mouse corpus cavernosum (CC). L-cysteine (endogenous H2S substrate; 10-6-10-3 M), sodium hydrogen sulfide (NaHS; exogenous H2S; 10-6–10-3 M) and acetylcholine (10-9-10-4 M) produced concentration-dependent relaxant responses in isolated mouse CC tissues pre-contracted by phenylephrine (5x10-6 M). Relaxations to endogenous and exogenous H2S were reduced by atropine (5x10-5 M), non-selective mAChR antagonist, pirenzepine (5x10-5 M), selective M1 receptor antagonist, and 4-DAMP (10-7 M), selective M3 receptor antagonist but not by AF-DX (10-6 M), selective M2 receptor antagonist. Also, acetylcholine-induced relaxations were reduced by atropine, pirenzepin and 4-DAMP but not by AFDX-116. Futhermore, D,L- propargylglycine (PAG, 10–2 M), a cystathionine-gamma-lyase (CSE) inhibitor and aminooxyacetic acid (AOAA, 10–3 M), a cystathionine-β-synthase inhibitors (CBS), significantly attenuated the relaxant responses to acetylcholine. In addition, the existence and localization of CSE, CBS and 3-MST were demonstrated in mouse CC. Also, acetylcholine levels were evaluated in the incubation medium of isolated CC strips. L-cysteine significantly increased the acetylcholine levels and this augmentation was significantly decreased in the presence of PAG and AOAA. However, exogenous H2S did not alter acetylcholine levels. We conclude that there is a crosstalk between L-cysteine/H2S pathway and mAChRs M1 and M3 but not M2 receptors in mouse CC. Also, CSE/CBS enzymes lead to acetylcholine release which is probably activates M1 and M3 receptors and might involve to this crosstalk.

Key words: acetylcholine, corpus cavernosum, H2S, L-cysteine, muscarinic receptors

Phytochemical Analysis and Biological Evaluation of Selected Cordia Species from PanamaKarikas GA1,*Marini G2, Graikou K2, ,Zengin G. 3, Gupta MP. 4, ChinouI.21Athens University of Applied Sciences, Greece 2University and Kapodistrian University of Athens, Greece3Selcuk University, Turkey4University of Panama, Republic of PanamaAbstract

The aim of the present study has been the phytochemical analysis of three tropical species of the genus Cordia (Boraginaceae) Cordia bicolor, C. megalantha, C.dentataand Cordia bicolor afforded 9 compounds, namely allantoin(1) , rosmarinic acid (2), caffeic acid (3), quercetin 3-O-β-D- glucoside (4), quercetin 3-(6’’-O-α-L-rhamnosyl)-β-D- glucopyranoside(5) quercetin -3-Ο-(2’’ rhamnosyl)-β- D glucoside (6),kaempferol -3-Ο- (2’’ rhamnosyl)_-β- D - glucoside (7), quercetin 3-O- (6’’ trans-p- coumaroyl)-β-D- glucopyranoside(8) and kaempferol3-O- (2’’-O-α-L- rhamnosyl- 6’’ trans-p- coumaroyl)-β-D- glucoside (9). Cordia megalantha yielded 2 compounds: rosmarinic acid (2) and quercetin 3-O-(6’’ trans-p- coumaroyl) –β- D-galactopyranoside(10), while six compounds have been isolated from Cordia dentata: quercetin 3-(6’’-O-α-L-rhamnosyl)-β- D- glucopyranoside (5), rosmarinic acid (2), caffeic acid (3), 4–hydroxyphenyl lactic acid (11), sitostenone(12) and sitosterole(13). Compounds (6) and (7) are isolated for the first time in the genus Cordia, while this is also the first report of compounds (8), (9) and (10) in the Boraginaceae family. The methanolic extracts of the plants were assayed for their antioxidant properties by different procedures including free radical scavenging, reducing power, phosphomolybdenum and metal chelating assays. Enzyme inhibitory activities of the extracts were also tested against cholinesterases, a-amylase and a-glucosidase, showing an interesting profile.Biography

George-Albert Karikas has completed Bachelor of Pharmacy in 1976, Ph.D. in Biochemistry/Pharmacognosy fromNational and Kapodistrian University of Athens, Greece (1981) and Ph.D. in Chemistry of natural products from University of Manchester, U.K. in 1986. From 1989-2007, he worked as Hospital pharmacist-Director of NHS, Children Hospital “Aghia Sophia”, at Athens, Greece. He has worked as a Visiting Professor of Pharmacognosy in Panama University from 1992-94. Currently he is working as a Professor of Biochemistry and Clinical Chemistry at Technological Educational Instituteof Athens (TEI), Greece. From 2015, he is the Director of Master program “Biomedical methods and technology in diagnosis”, Medical Laboratories Technology Dept., at Technological Educational Institute of Athens. He is a member and reviewer in many scientific societies and journals. He has published/cited numerous articles in peer journals and presented in national and international conferences.

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