7^th Euro-Global Summit on Toxicology and Applied Pharmacology October 24-26, 2016 Rome, Italy

Biography:

Susanne Bremer Hoffmann holds a PhD degree in Biology obtained for her work on the development of immunotherapies against leukemia. After Post-doctoral Research at the Federal Institute for Risk Assessment in Germany, she joined the Joint Research Centre of the European Commission and became a Team Member of the European Centre for the Validation of Alternative Methods (EURL-ECVAM) where she was involved in validation studies of toxicological in vitro tests. She collaborated in several framework projects including public-private partnerships and is now a Team Member of the EU-NCL assessing the toxic potential of nanomaterials by using in vitro test.

Abstract:

In 2013, the World Health Organization (WHO) released an update of the report on “Priority Medicines for Europe and the World” with the aim to bridge the gap between public health needs and the current research and development priorities. The European Commission has recognized the opportunities off ered by nanotechnology in the health care sector for the development of new diagnostic/therapeutic concepts and funds a wide range of projects in order to fully exploit the potential of nanotechnology. Th ese research activities generate ideas, knowledge and prototypes addressing unmet medical needs that
need now to be further progressed into clinical applications. In order to support the translation of such nanomedicines towards clinical use, the European Nanomedicine Characterization Laboratory (EU-NCL) has been established. Th e EU-NCL provides a comprehensive set of characterization tests (physical, chemical, in vitro and in vivo biological properties) allowing researchers and SMEs to better defi ne critical quality and safety attributes of their products before entering into clinical investigations. The knowledge base generated by the EU-NCL will additionally support competent authorities to further understand regulatory needs of this emerging product category and will boost the regulatory science in the field.

Biography:

Bulent Ozpolat is an Associate Professor at the Department of Experimental Therapeutics at MD Anderson Cancer Center, Houston, TX, USA. He earned his PhD degree in Immunology from The University of Texas, M.D. Anderson Cancer Center, Houston Graduate School of Biomedical Sciences after getting his MD degree from The University of Dokuz Eylul University, Izmir, Turkey. He completed his graduate and Post-doc Training at the departments of Cancer Biology and Immunotherapy at MD Anderson Cancer Center. His research focuses on identifi cation of novel survival pathways including EF2-Kinase (eEF2K) and autophagy pathways as well as regulation of cell death mechanism such as autophagic and apoptotic cell death; and development of molecularly targeted therapies using tumor-targeting nanotherapeutics (i.e. liposomes, immunoliposomes and metal-magnetic nanoparticles) in aggressive type of solid tumors (i.e. breast, pancreatic and ovarian cancers) and hematological cancers such as leukemia and lymphoma for the delivery of therapeutic cargo including siRNA, microRNA small molecule inhibitors, peptides, proteins, cytokines and anticancer agent. He is a Member of Center for Targeted Therapy and Non-Coding RNA Center and received many research awards in recognition of research excellence. He has published more than 50 papers, 9 book chapters and 12 review articles in peer-reviewed high impact journals and contributed to textbooks.

Abstract:

Triple-negative breast cancer refers to any breast cancer which is clinically characterized as more aggressive and less responsive to standard treatments, and is associated with poor overall patient prognosis. Th erefore, there is an urgent need to develop eff ective and safe therapies against triple negative breast cancer due to poor prognosis and lack of targeted therapies. Recently, we found that EF2-Kinase (EF2K) is signifi cantly overexpressed in breast cancer cell lines compared with normal breast epithelium and its expression is associated with poor patient overall survival. However, its regulation and the
role in breast cancer progression and tumorigenesis are not known. We demonstrated, for the fi rst time, that inhibition of EF2K blocked proliferation, colony formation and invasion and tumorigenesis of TNBC tumors. We also discovered that FOXM1 and a microRNA directly binds and regulates EF2K gene expression and targeting of these molecules recapitulates the eff ects of
EF2K targeting inhibit proliferation, invasion migration and tumor growth in TNBC models. We demonstrated blocked tumor growth tumor xenograft s and signifi cantly enhanced the in vivo effi cacy of chemotherapy. Inhibition of FOXM1-miRNA/eEF2K axis signifi cantly reduced Src/Fak/Paxillin, IGF-1R, PI3K/Akt/mTOR, cyclinD1, c-myc, HIF1 alpha and VEGF and induced
significant apoptosis in tumors. Overall, our studies suggest that EF2-Kinase plays an important role in TNBC tumorigenesis and progression and EF2K targeted therapies provide the proof of concept for translation into Phase-I clinical trials in patients.

Biography:

Gerd Bode, holds board certified specializations in Pathology, Neuropathology, Legal Medicine, Pharmacology and Toxicology. After his university career he was head for Drug Safety and Pharmacovigilance at Boehringer Mannheim (Germany), then head of Lead Optimisation (Pharmacology, Toxicology, Kinetics, Metabolism and Clinical Phase I) at Hoechst Marion Roussel/Aventis (Paris/France). And finally head of preclinical research and development of ALTANA Pharma AG, Germany (Hamburg) until 2005. He serves as lecturer at several German, Swiss and French universities. He was for the European Industry (EFPIA) ICH-Topic Leader for Preclinical Safety Guidelines from 1989 to 2005 in the International Conferences on Harmonisation. He works now as a lecturer and independent consultant.

Abstract:

Rodent carcinogenicity studies are not meant to produce a toxicology result/tumor count, but to extrapolate (translate) these data and develop a prediction of potential cancer risk for patients. If there is a real risk, then either no approval can be granted or a rigid risk/benefi t analysis will justify any treatment of humans. Altogether, there are too many positive results from such long-term rat or mouse studies. Th e need for the 2 year rodent assay to assess a carcinogenic potential is questioned already for years. From retrospective analyses of various datasets (PhRMA, FDA, JPMA and common EU+FDA) it was concluded that based on genotoxicity and non-genotoxic mechanisms, detectable in pharmacology and chronic toxicity data (usually present at the end of phase 2 in the development of a new pharmaceutical) the outcome of
the 2-yr rat carcinogenicity study can be predicted with reasonable assurance at the two extremes of the spectrum: Negative predictions can be made when predictive carcinogenic signals are absent and positive predictions are possible when such signals are present. In between a category of compounds still remain for which the outcome cannot be predicted with sufficient certainty and where experimental studies may have added value to identify real hazards. Th ese hypotheses are being tested in an ongoing common exercise by agencies and industries. Such prospective evaluations are necessary to justify any revision of the present recommendations of the ICH guideline S1. Until 2017, sponsors will be strongly encouraged to submit carcinogenicity assessment documents (CADs) to drug regulatory agencies (DRAs) for all investigational pharmaceuticals with ongoing or planned 2-yr rat carcinogenicity studies. Th e CAD would address the overall carcinogenic risk of the investigational drug as predicted by the available knowledge and a rationale for why the conduct of long-term studies would or would not add value to that assessment, in the latter case by a request of a “virtual” waiver. Drug regulatory agencies will independently review the submitted documents and evaluate the degree of concordance with sponsors. During this prospective evaluation period waiver requests will not be granted but the data are intended solely for collecting
experience. Submitted CADs will fi nely be compared to the real outcome of the 2-yr carcinogenicity studies and/or any other factors of a weight of evidence evaluation. Main objective will be the assessment of accuracy of the predictions, with emphasis on the “Virtual” waivers. Th is paper will inform about the details of the retrospective analyses leading to the new hypothesis
and will report about preliminary results of this prospective exercise. Hopefully, further contributing participation can be
stimulated.

Biography:

Abstract:

Especially high health risks associated with impacts of metallic and metal oxides nanoparticles (Me-NPs) contaminating working environments of not only the emerging nano-industry but also of some long-existing traditional technologies makes it necessary, along with keeping respective dangerous exposures as low as possible, to look for ways of increasing the organism’s resistance to them (the “biological prophylaxis”). Th eoretical premises of beneficial interventions in toxicokinetics and toxicodynamics of Me-NPs are inferred from understanding general and specifi c key mechanisms of their adverse action and on our previous experience in the fi eld of such bio-protection against other toxics. Based on these premises, we proposed
several “bio-prophylactic complexes” (BPCs) comprising mainly pectin, some vitamins, glutamate, glycine, N-acetylcysteine, omega-3 PUFA and diff erent essential trace elements. Results of several in vivo experiments with NPs of metallic silver and of copper oxide as well as with binary and trinary combinations of Me-NPs characteristic of workroom air pollution in diff erent
industries have proved that, against the background of such BPCs’ oral administration, the pulmonary and systemic toxicity of Me-NPs and even their genotoxicity can be markedly attenuated. Th erefore, we recommend to further develop this vector of nano-toxicological research. Our previous positive experience in organizing fi rst a selective and then a large-scale biological
prophylaxis of adverse health eff ects of many other toxicants makes us expect that it would be no less practicable and effective in the field of nano-toxicology as well.

Biography:

James Dahlgren, MD, is a Board Certifi ed Internist Retired Assistant Professor from UCLA School of Medicine. He has been in Private Practice of internal medicine with a sub specialty in toxicology for over forty years. He has studied and treated thousands of patients with toxic chemical injuries including numerous victims of toxic chemical poisoning including the subjects dramatized in the Erin Brockovich movie. He has been treating and evaluating people with exposures of oil field chemicals since the 1970’s.

Abstract:

The oil refi nery located in Hooven, Ohio operated from 1931 to 1986 producing gasoline, jet fuels, diesel, home-heating oils and sulfur. Th e refi nery has a history of leaks, spills, fi res, explosions and air pollution while operating. Dozens of nearby residents sustained exposures to odors and emissions from numerous accidental releases and fires while the plant
was operating. Aft er the plant closed, continuing exposure included contaminated soil and ground water that led to massive vapor intrusion and air pollution. Many homes had monitoring wells in the basements that documented the presence of shallow pools of liquid petroleum. Environmental investigations revealed a large (236 acre) plume of non-aqueous liquid
phase hydrocarbons (80% gasoline) fl oating on the groundwater beneath the village of Hooven in 2003. Ground water testing beneath homes in the 1990’s revealed benzene at maximum levels of 3.6 PPM. Soil vapor levels were not available. We present 4 cases of lymphohematopoietic cancers in residents who lived in the air plume and had documented exposure to low levels of
benzene. All 4 individuals resided for years within a few hundred yards of the refinery. Th ere were 2 cases of multiple myeloma, 1 case of acute myeloid leukemia (AML), and Hodgkin’s lymphoma. Modeled levels of benzene ranged from 0.125 to 3.12 PPM years. Th ese levels of exposure are consistent with the current research on environmental exposure and blood cancers. A study
by the state revealed a signifi cant excess of other cancers in the area.

Biography:

Pieranna Chiarella has completed her PhD at the Department of Histology and Medical Embryology from Sapienza University of Rome and worked as Post-doc at the University of Rome Campus Bio-Medico and as Staff Member at the European Molecular Biology Laboratory. She is currently Researcher at INAIL, Department of Occupational and Environmental Medicine, Epidemiology and Hygiene in Monte Porzio Catone (Rome-Italy).

Abstract:

Several genes encoding for enzymes involved in xenobiotic biotransformation and oxidative stress response have been shown to be polymorphic within the human population. These genes are particularly noteworthy in the occupational
toxicology field being useful to identify individuals with higher susceptibility to specific toxic agents, allowing implementation of measures to reduce the exposure risk. Although blood is the fi rst choice biological matrix to extract genomic DNA, there are some critical issues hindering its use in occupational studies: 1) blood draw invasiveness 2) diffi culty to achieve consent
from donors 3) need of the authorized medical doctor for blood sample collection 4) safety issues during blood processing 4) time-length of cell isolation procedure. Since urine is the routine sample used in the bio-monitoring of occupational exposure to chemical agents, the use of the same sample would be advantageous for both purposes, i.e. biomarker determination and genotyping. Here we report an eff ective method to isolate genomic DNA from urinary sediment. Th e protocol is not based on
use of commercial kit, is cheap, rapid and allows determining the genotypic status of individuals using PCR and RFLP analysis. Before applying this procedure to exposed workers, we tested the effi cacy on urine harvested from our institute donors and carried out genotyping analysis of GSTT1 and GSTM1 enzymes. In conclusion, at least for the genotyping analysis, urine sediment represents a suitable alternative to whole blood. Th is approach might be extended further to identify specific gene and protein biomarkers of dose/exposure in the occupational and environmental setting.

Biography:

Yazan Akkam has completed his PhD from University of Arkansas and Post-doctoral studies on Nanotoxicity from Institute for Nanosciences and Engineering, Arkansas. He is the Head of Department of Pharmaceutical Sciences, Faculty of Pharmacy, Yarmouk University, Jordan. Also, he is a Member of the National Committee for the Management of Nanomaterials- Ministry of Environment, Jordan.

Abstract:

Graphene possesses physical characteristics ideal for next-generation electronic and photonic devices and is being explored for medical applications in drug delivery, photo-thermal therapy, and bionic devices. Oxidation and functionalization of graphene changes its dispersion in aqueous medium and provide methods to tailor its functional properties. The aim of our study is to evaluate the safety of commercial graphene (CG) and functionalized graphene (FG) by taking advantage of 2 genetically tractable eukaryotic models: Saccharomyces cerevisiae and Candida albicans. Th e CG and FG samples were characterized by X-ray photoelectron spectroscopy, scanning electron microscopy and atomic force microscopy. Further, the toxicity of CG and FG were tested using various assays, including cell growth and cell viability. Cell growth was measured via microdilution assay, spot plating and measurement of optical density. Cell viability was investigated using various metabolic
assays, propidium iodide staining and growth curves. X-ray photoelectron spectroscopy confi rmed the oxidation of CG to FG, and determined the percentage of oxidation. Atomic force microscopy was used to determine the average size of the graphene particles, while scanning electron microscopy provided a view of particle morphology. All cell growth assays demonstrated
that FG, but not CG, interfered with the growth of both yeast species in a dose-dependent manner. Furthermore, our data suggests that exposure of cells to FG, but not CG, is toxic and leads to loss of cell viability. Our next goal is to understand how cell exposure to FG may infl uences genome-wide gene expression, thereby revealing cellular activities sensitive to FG exposure.

Biography:

José Fernando Santos Almeida is a Psychiatrist and completed his PhD from Instituto de Ciências Biomédicas Abel Salazar (Universidade do Porto). He is a
Professor and President of Scientifi c Council of Instituto Universitário da Maia and Editor-Chief of Psiquiatria, Psicologia & Justiça.

Abstract:

There are clinical variables related to severe violence by mentally ill as hostility, behavior infl uenced by the hallucinatory activity, grandiosity- with unrealistic belief of superiority, the delirious activity of suspicion/persecution and accelerated motor behavior hyperactivity, highly responsive to stimuli and hyperarousal or excessive instability. Other important factors to match, when we address violence committed by these patients are substance abuse, premorbid personality and ecological problems, namely, the quality of life in the family. Falk et al. concluded that persistent violence was associated with male gender, personality disorder, convicted of a violent crime before the age of 19, off enses related to drugs, non-violent crime, substance use and mental disorder. Th e decrease in consumption of substances is very important when we want to prevent criminal recidivism of these patients even when patients are set free after serving a safety measure for a crime they have committed. In order to prevent criminal recidivism when they were released, we implemented a psychiatric care intervention with these patients.

Biography:

Samuel Legeay is a PharmD PhD student at the University of Angers in France (west part of France). He worked mainly on two different subjects: In USA at
Augusta University (Georgia) on the regulation of hypertension in diabetic conditions and at the University of Angers (France) on the impact of mosquito repellents in angiogenesis. He has 2 published articles in PubMed and 1 book chapter and is a member of the French Society of Pharmacology and Therapeutics.

Abstract:

The insect repellent N,N-diethyl-m-toluamide (DEET) has been reported to inhibit AChE (acetylcholinesterase) and to be associated with increased risk of cancer. In the present paper, we demonstrate that DEET specifi cally stimulates
endothelial cells that promote angiogenesis which increases tumor growth in vivo. DEET activates cellular processes that lead to angiogenesis including proliferation, migration and adhesion. Th is is associated with an enhancement of NO production and VEGF expression in endothelial cells. M3 silencing or the use of a pharmacological M3 inhibitor abrogates all of these effects which reveals that DEET-induced angiogenesis is M3 sensitive. Th e experiments involving calcium signals in both endothelial and HEK cells overexpressing M3 receptors, as well as binding and docking studies demonstrate that DEET acts as an allosteric modulator of the M3 receptor. In addition, DEET inhibited AChE which increased acetylcholine bioavailability and binding to M3 receptors and also strengthened pro-angiogenic eff ects by an allosteric modulation.

Biography:

Cédric Wernli worked for about 10 years as a Lab Technician in the Clinical Chemistry laboratory in Toxicology department at the University Hospital in Basel. After his studies in Pharmacy at University of Basel (MSc in Pharmacy, 2013), he passed the board exam as a Pharmacist in October 2013. Since then, he works as a PhD-student at the University of Basel in coorperation with the University of Applied Science and Arts Northwestern Switzerland in developing quantitative lateral flow immunoassays for therapeutic drug monitoring in whole blood.

Abstract:

Introduction: An enzymatic assay for quantifi cation of γ-hydroxybutyric acid (GHB) in biofl uids can be employed for targeted
screening of succinic semialdehyde dehydrogenase defi ciency (SSADHD) in selected populations. We used a two-tiered study
approach, in which the fi rst study (proof of concept) examined seven urine samples derived from patients with SSADHD and
fi ve controls, and the second study (feasibility study) examined a broader sample population of patients and controls, including
plasma.
Objective: Aim of this study was to evaluate split samples of urine and plasma (anonymized) by enzymatic assay, gas
chromatography alone (proof of concept) and gas chromatography-mass spectrometry, and the results compared.
Method: Multiple detection methods have been developed to detect GHB. We evaluated an enzymatic assay which employs
recombinant GHB dehydrogenase coupled to NADH production, the latter quantifi ed on a Cobas Integra 400 Plus.
Results: In our proof of concept study, we analyzed 12 urine samples (fi ve controls, seven SSADHD) and in the feasibility study,
we evaluated 33 urine samples (23 controls, 10 SSADHD) and 31 plasma samples (14 controls, 17 SSADHD). Th e enzymatic
assay carried out on a routine clinical chemistry analyzer was robust, revealing excellent agreement with instrumental methods
in urine (GC-FID: r=0.997, p ≤ 0.001; GC-MS: r=0.99, p≤ 0.001); however, the assay slightly over-estimated GHB levels in
plasma, especially those in which GHB levels were low. Conversely, correlations for the enzymatic assay with comparator
methods for higher plasma GHB levels were excellent (GC-MS; r=0.993, p≤ 0.001).
Conclusion: We have evaluated the capacity of this enzymatic assay to identify patients with SSADHD via quantitation of GHB.
Th e data suggests that the enzymatic assay may be a suitable screening method to detect SSADHD in selected populations
using urine. In addition, the assay can be used in basic research to elucidate the mechanism of the underlying disease or
monitor GHB-levels for the evaluation of drug candidates.

Biography:

Hanan Osman Ponchet has completed her PhD from University of Burgundy (France) and Post-doctoral studies from University Hospital of Geneva (Switzerland) and National Institute of Agronomy Research (France). She is currently Metabolism Manager in the Department of Drug Metabolism and Pharmacokinetics at Galderma, a global dermatology company. She has more than 15 years of experience in DMPK and has published more than 30 research publications and patents, and has given invited oral presentations at several different scientific conferences.

Abstract:

Most identified drug transporters belong to ATP-binding cassette (ABC) and solute carrier (SLC) families. It has been recently recognized that like drug metabolizing enzymes, some of drug transporters play an important role in pharmacokinetics and drug exposure and may be involved in clinically relevant drug-drug interactions for systemic drugs. However very little is known about the role of drug transporters in human skin in the disposition of topically applied drugs. Expression profi le of SLC and ABC transporters included in the regulatory guidelines as the most likely clinical sources of drug interactions was characterized in ex vivo human skin using TaqMan real-time RT-PCR. Moreover, the eff ect of rifampicin treatment and solar simulator irradiation on the expression of drug transporters in human skin was investigated as well as the localization of the drug transporters within the diff erent layers of human skin. SLC and ABC transporters have a very specific expression profile in human skin compared to liver and kidney. In addition, expression of ABCC1 (MRP1) and SLC47A1/2 (MATE1 and MATE2) is shown for the fi rst time in human skin. Th e role of drug transporters in drug absorption in human skin will be presented and discussed.

Biography:

Liping Yang has completed her PhD from RMIT University in Australia. She is the Vice-Director of Pharmacy Department, Beijing Hospital, a large-scale general hospital. She has published more than 90 papers in reputed journals and has been serving as an Editorial Board Member of repute. Since 2003, she has served as a Clinical Pharmacist, Senior Clinical Pharmacist, Associate Professor and Professor for the Pharmacy Department, Beijing Hospital, China. Her major interests are pharmacogenomics, drug-drug interaction, evidence-based medicine, Chinese medicine and rational drug use in clinical setting.

Abstract:

Background & Objective: Th e glycopeptide antibiotics, vancomycin and teicoplanin, are the mainstay of therapy for severe gram-positive organisms such as methicillin-resistant Staphylococcus aureus. We report a case of Stevens–Johnson syndrome (SJS) induced by sequential therapy with teicoplanin and vancomycin, in a patient with chronic obstructive pulmonary disease (COPD).
Case Summary: A 74-year-old Han Chinese with 1-year history of COPD was admitted for treatment of infective endocarditis.
Aft er teicoplanin therapy for 12 days, he developed pruritus and maculopapular over his trunk and limbs. His rash spread
rapidly to most parts of the body surface area, 7 days aft er his anti-infection therapy was switched to vancomycin. Th is was stopped, but he developed SJS when teicoplanin was reintroduced. Th is patient recovered from his drug eruptions when both teicoplanin and vancomycin were stopped. Pharmacogenetic analyses revealed he was heterozygous with respect to 2 variants (rs2844682 of MUC21 and rs750332 of BAG6).
What is new & Conclusion: Cross-reactivity between vancomycin and teicoplanin is rare. SJS attributable to sequential treatment with these 2 antibiotics has not been reported previously. Care should be taken when prescribing vancomycin in patients with a previous documented skin eruption to teicoplanin, especially in those who carry any susceptibility alleles to
SJS/TEN.

Biography:

Marcel Gubler received his PhD in Life Sciences at the Federal Institute of Technology (Zürich, Switzerland) in 1988, followed by 2-years Post-doctoral Fellowship at the Massachusetts Institute of Technology (Cambridge, MA). Subsequently, he joined Preclinical Research at F. Hoffmann-La Roche Ltd (Basel, Switzerland), where he worked on novel targets for antibacterial therapies. In 2000, he changed to the Department of Metabolic Diseases to focus on drug treatments for obesity, diabetes and renal diseases. Since 2014, he has been investigating mechanisms of renal toxicity of different drug modalities in the Department of Drug Disposition and Safety, F. Hoffmann-La Roche Ltd.

Abstract:

Chronic treatment of patients with classical low molecular weight drugs like aminoglycoside antibiotics, antivirals and immune-suppressants are known to induce kidney toxicities. Particularly molecules with high renal clearance
can accumulate in proximal tubule epithelial cells (PTECs) of the kidney cortex where high tissue concentrations induce damage to tubular structures and may lead to loss of organ function. Similar toxicities have also been observed with other drug modalities such as for example some single stranded oligonucleotides (SSOs). SSOs represent a class of novel drugs to
modulate gene expression in many diff erent diseases for which there is no adequate treatment currently available. In order to secure development of renal safe drugs, we have established assays with animal and human primary as well as immortalized PTECs for profi ling of nephrotoxic reference compounds side-by-side with SSOs that had previously been tested in rats for signs of organ damage. Using assays of cell function, viability, and death, we have been able to clearly discriminate safe from toxic molecules. Overall, the observed eff ects were similar across PTECs derived from animals and humans and correlated with the in vivo fi ndings for the molecules tested in rats. Th us, we believe that our cellular assays will be useful for rapid in vitro profiling of SSOs for selection of safe compounds on human cells prior to clinical testing.

Biography:

Manju Sharma is an MD and Doctor of Naturopathy working currently as a Scientist at Vancouver Prostate Centre, Vancouver General Hospital, Canada for the last 10 years. Prior to this, she worked in the Department of Pathology and Lab Medicine, VGH for 10 years on various projects including molecular diagnosis of tuberculosis, multi-drug resistant tuberculosis, human solid tumors, kidney disorders, medicinal herbal plants like Echinacea which is widely used all over Europe and North America for the treatment of cough and cold: Active principles and their mode of action on various human viral and bacterial diseases. She has published over 75 papers in medical journals and has made several presentations in the fi eld of Medicine.

Abstract:

Psoriasis, a chronic infl ammatory skin disease marked by hyper-proliferation and aberrant diff erentiation of keratinocytes, affects 2-3% of the population in the United States. Research into the pathogenesis of psoriasis has been hampered by the lack of animal models that accurately refl ect the biology of psoriatic phenotype. We have previously reported that EISO has significant anti-infl ammatory properties in skin models. We hypothesized that EISO might provide therapeutic benefit to psoriasis patients due to its anti-infl ammatory and anti-proliferative properties. Th e clinical relevance of this hypothesis is supported by interim results from an on-going proof-of-concept Phase 2 clinical trial in which topically applied EISO is demonstrating to be well tolerated and helpful in alleviating mild to moderate psoriasis symptoms. We have evaluated the ability of EISO to aff ect the psoriatic phenotype using organotypic psoriasis tissue and normal (non-psoriatic) human skin models
from MatTek Corporation. Treatment of the psoriasis tissue model with EISO reverted psoriatic pathology, as demonstrated by histologic characterization and expression of keratinocyte proliferation markers, Ki67 and psoriasin. Th ese phenotypic affects correlated with greatly suppressed production of ENA-78, IL-6, IL-8, MCP-1, GM-CSF and IL-1β. Demonstration of the ability
of EISO to abrogate these psoriasis symptoms in well-characterized in vitro psoriatic tissue models supports the hypothesis that the clinically observed symptom alleviation is due to suppression of intrinsic tissue infl ammation reactions in afflicted lesions. This study presents systems to further study the underlying mechanisms that cause psoriasis, and to help direct and accelerate
the development of more eff ective therapies.

Biography:

Frieder Keller has completed his MD and Post-doctoral studies from Free University, Berlin. He was Head of Nephrology Division at Ulm University and is
a Teacher in Clinical Medicine. He has published more than 250 papers in PubMed cited journals and is serving as an Editorial Board Member of Clinical
Nephrology.

Abstract:

Background: The therapeutic window between effi cacy on the one side and toxicity on the other side is very narrow for many immunosuppressive, anti-viral and anti-cancer drugs. The present contribution is to review the literature data and our own experience with regard to the value of a leukocyte monitoring for effi cient drug therapy.
Methods: If there is leukocytopenia at least an eff ect can be assumed. Since the benefi cial eff ect and the adverse effect are
frequently better correlated than the drug concentration and the target eff ect, monitoring of leukocytes might be more cost-eff ective than monitoring of drug concentrations. A selective PubMed research was undertaken, therefore, to look for publications where the monitoring of leukocytes is used for targeting the drug dose.
Results: The use of cyclophosphamide has been successfully introduced for treatment of systemic vaxculitis by adjusting the dose to the leukocyte count. A leukocyte nadir was found to indicate a better prognosis in lung cancer and testicular cancer patients. A better outcome has been associated with cancer chemotherapy targeting neutropenia than with lower dose. This is in agreement with our own experience on the intravenous cyclophosphamide pulse therapy in IgA nephritis. This regimen applies also to the monitoring of azathioprine or mycophenolate and to ganciclovir and valganciclovir or cidofovir. However, a
threshold nadir for leukocyte count must be defi ned to avoid persistent agranulocytosis.
Conclusion: Leukocytopenia is an eff ect of immunosuppression, of anti-viral or anti-cancer drug therapy. This easy to measure lab parameter can be used for pharmacodynamic monitoring of the effi cacy of the critical dose drug therapy.

Biography:

Halef Okan DOÄžAN graduated from Ankara Numune Education and Research Hospital as a Clinical Biochemist in 2013. He is a biochemistry laboratory director in the Cumhuriyet University, School of Medicine. He has published 9 papers in different scientific journals. 

Abstract:

In this study, we evaluated the effect of prenatal PCB toxication on oxidatant and antioxidant status in the central nervous system  (CNS) tissues and the protective effect of curcumin. Animals were divided into a control group and 2 experimental groups. Group 1 (n=10) was considered as a control group. In group 2 (n=10) we exposed the pregnant  rats to PCB mixture.  In group 3 (n=10) we exposed preganat rat to PCB mixture and curcumin. We measured  plasma neuron specific enolase (NSE) concentrations in all pups. We also measured  total antioxidant status (TAS) level and total oxidant status (TOS) level in the tissue (brain, cerebellum, pons and medulla oblongata) homogenisats of CNS. In this study the TOS level was found higher in brain and cerebellum in group 2 and 3 than control group. However, we did not find any change in TOS and TAS level in medlulla oblongata and pons in group 2 and 3. The concentration of NSE was higher in group 2 than control group. We also found that the use of curcumin had not any effect on the TOS and TAS concentrations. In conclusion; the main effected part of the central nervous systems are brain and cerebellum  in terms of TOS concentrations. We did not find any effect of curcumin to increase TAS concentrations and decrease the concentration of TOS in brain and cerebellum.  Additionally, NSE can be used as a useful biomarker to deterimne the  damages found  in the CNS in case of prenatal PCB toxicaiton.

Biography:

Anna Radominska Pandya serves as a Professor in the Department of Biochemistry and Molecular Biology at UAMS; and she is the Editor in Chief for Drug Metabolism Review. She received her PhD from the Institute of Biochemistry and Biophysics, Polish Academy of Sciences in Warsaw, Poland. She has published 175 papers in various peer-reviewed journals, and she has received twelve R01 grants from the NIH and DoD. Her research interests include: The regulation and suppression of human UGTs and their role as anti-proliferative agents in cancer models, the interactions between UGTs and cannabinoid receptors, the delivery of UGT genes and drugs into cancer cells using nanomaterial, and the roles of UGTs in the biotransformation of drugs including resveratrols and drugs of abuse such as marijuana and synthetic cannabinoids.

Abstract:

K2, also called “Spice” or “Synthetic Marijuana,” is a rapidly emerging drug of abuse that possesses psychoactive properties similar to those of Δ9-tetrahydrocannabinol (Δ9-THC). K2 use has exploded in many sections of the population including teenagers and fi rst time drug users. Use of K2 can result in extreme agitation, hallucinations, supraventricular tachycardia, syncope and seizures. The presence of more than 20 diff erent K2-aminoalkyl indoles (AAIs) have been reported in various K2s, but the two most commonly observed are JWH-018 and JWH-073; however, new generations of structurally related compounds are constantly being produced. Our studies demonstrate for the fi rst time that the native K2s undergoes extensive metabolism by cytochrome P450s and UDP glucuronosyltransferases. Due to the activity of these enzymes, a variety of hydroxylated metabolites, have been biosythesized and excreted in human urine primarily as glucuronidated conjugates. These
metabolites were identifi ed and characterized using LC-MS/MS and HPLC-UV/Vis, and steady state kinetic analyses were also investigated. We have also shown that these K2 products cause psychoactive eff ects similar to those of Δ9-THC by activating CB1 cannabinoid receptors (CB1Rs) in the central nervous system. Moreover, CBRs were able to bind several hydroxylated and glucuronidated K2-AAI metabolites with an affinity similar to that of the parent compound. Finally, our in vivo data demonstrates that K2 metabolites retain biological activity in mice. The fact that some hydroxylated derivatives and their glucuronides can retain their biological activity makes the study of these compounds essential for understanding their severe toxicity and pharmacokinetics/dynamics. We hypothesize that the severe effects observed for some K2 users could be related to a defect in their metabolism.

Biography:

Mahmoud M El Mas completed his PhD in 1990 from Joint Scheme between Leeds University, UK and Alexandria University, Egypt. He pursued Post-doctoral Training at East Carolina University, USA. He is Chair of Pharmacology and Toxicology, Pharmacy, Alexandria University, Egypt and Chair of National Scientific Committee on Pharmacology Faculty Promotion. His publications include: 107 papers in top international journals and 90 abstracts in international conferences. His research expertise is: Cardiovascular/renal neurobiology of drugs of abuse (ethanol, nicotine) and immune-suppressants. He holds Editorial Board positions in 9 international journals. His Awards are: Khalifa Award for Education in the Field of Scientific Research (United Arab Emirates), State Prize for Scientific Encouragement (twice), State Prize for Scientifi c Excellence, ACDIMA award (Jordon), Alexandria University Honorary Award.

Abstract:

The combined use of cyclosporine (CSA) and nonsteroidal anti-infl ammatory drugs (NSAIDs) in arthritic conditions is common in clinical practice. Because CSA or NSAIDs negatively impacts cardiovascular/renal functions when used
individually, we asked if these two drug modalities would provoke more detrimental consequences when used together. The roles of endothelin receptor, inflammatory and fi brotic pathways in these interactions have also been investigated. The treatment of rats with celecoxib, but not indomethacin, blunted the CSA-evoked increases in blood pressure (BP), renal perivascular fi brosis and arteriolar endothelin receptor expression (increases in ETA and decreases in ETB receptors). Alternatively, exaggerated nephrotoxicity was seen upon simultaneous treatment with CSA plus indomethacin as evidenced by greater elevations in serum creatinine and renal oxidative stress; renal infiltration of infl ammatory cells and worsening of fi brotic and necrotic
profi les; and increased renal ET-1 and COX-2 expression. Unlike indomethacin, renal structural, oxidative, and molecular abnormalities caused by CSA were largely eliminated in rats treated concurrently with celecoxib. ETA receptor blockade by atrasentan ameliorated the hypertension and concomitant renal abnormalities caused by CSA/indomethacin regimen. On the other hand, ETB receptor blockade (BQ788) caused celecoxib-sensitive hypertension and renal dysfunction and potentiated the hypertensive eff ect of CSA. These fi ndings suggest that COX-1/COX-2 selectivity of NSAIDs is pivotal for identifying their cardiovascular and renal impacts on CSA toxicity. Celecoxib, but not indomethacin, is more advantageous as an add-on therapy to CSA for arthritis management. The reliability of the current experimental findings needs to be corroborated with appropriate clinical investigations.

Biography:

Christopher Dalton is a Principal Scientist at Defence Science Technology Laboratory (Dstl) in UK. He completed his BSc (Chemistry), MSc (Toxicology) and PhD (Toxicology) at University of Birmingham, England, UK. His research interest includes “The percutaneous penetration of chemicals”. He is a Chartered Biologist and European Registered Toxicologist.

Abstract:

Diffusion cells are used to determine the penetration of chemicals through skin in vitro. The cells have a limited surface area defined by the edge of the donor chamber. Should the penetrant spread rapidly to this containment limit the penetration rate can be accurately quantifi ed. For the hazard assessment of small droplets of toxic chemicals, such as cholinesterase inhibitors, limiting skin surface spread in vitro could lead to underestimation of percutaneous penetration and hence underestimation of systemic toxicity in vivo. The current study investigated the dependency of the percutaneous penetration of undiluted radiolabelled nerve agents [VX and soman (GD), 10μl] on skin surface spread (pig and guinea pig) using Franz-type glass diffusion cells with an area available for diffusion of either 2.54 cm2 or 14.87 cm2. Both VX and GD spread to the edge of 2.54 cm² cells, but not to the 14.87 cm² cells over the study duration. Amounts of VX and GD penetrating pig and guinea pig skin
in the 2.54 cm² cell were less than in the 14.87 cm² cell (except for GD under unoccluded conditions), however, penetration rates expressed per unit area were similar. Artificial limitation of skin surface spread in vitro does not impact percutaneous penetration in vitro as long as penetration is expressed in terms of mass per unit area.

Biography:

Sandip Mukherjee received his PhD degree in the year 2007 from Jadavpur University, Kolkata, India and has published over 24 research articles and book
chapter. He is an Assistant Professor (Senior Grade) at Department of Physiology, Serampore College since 2008. He has been serving as Reviewer in different
international journals with repute.

Abstract:

Cigarette smoking in regular habits aff ects our bodies in various ways and nicotine is the more abundant and most significant components of cigarette smoke. Epidemiological evidence strongly suggests an association between cigarette smoking and pancreatic injury. However, effects of cigarette smoking on pancreatic islets are still controversial. Impact and underlying mechanism of actions of folic acid and vitamin B12 on nicotine induced damage in pancreatic islets of rats are examined in the present study. Male Wister rats were exposed to nicotine with or without supplementation of folic acid and vitamin B12. Folic acid and vitamin B12, in combination, blunted the nicotine induced impairment in glucose tolerance, and levels of HbA1c and insulin in rats. Pro-infl ammatory cytokines like TNF-α and IL-6, generation of reactive oxygen species, nitric oxide production and other oxidative stress parameters were also attenuated by folic acid and vitamin B12 in nicotine treated rats. Both, folic acid and vitamin B12 in combination also limits the nicotine induced changes in cell cycle and excessive apoptosis of the pancreatic β-cell along with altered Bcl-2, Bax, caspase-3 and caspase-9 expression and up regulation of iNOS and TNF-α. Nicotineinduced alteration in loss of mitochondrial membrane potential (Δψm) and release of cytochrome c also reversed by folic acid and vitamin B12 supplementation. In conclusion, folic acid and vitamin B12 protects against islet cellular oxidative stress, which is a critical step in nicotine-mediated islet injury, and improves islet cell functional status by scavenging free radicals, inhibiting the generation of pro-infl ammatory mediators and apoptosis.

Biography:

Alan Poole earned his PhD from the University of Surrey and is a Fellow of the Royal College of Pathologists. He worked for the UK Medical Research Council
before moving to Smith Kline and French to lead a team involved in preclinical development of pharmaceuticals. He was later employed by Dow Chemical in
Switzerland where he worked addressing safety of industrial chemicals. He has published widely and is currently the Secretary General of the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC).

Abstract:

The extended one-generation reproduction toxicity study (EOGRTS; OECD test guideline 433) is a new and technically complex design to evaluate the putative eff ects of chemicals on fertility and development, including eff ects upon the developing nervous and immune systems. In addition to off ering a more comprehensive assessment of developmental toxicity, the EOGRTS provides important improvements in animal welfare through reduction and refi nement of use of experimental rodents in a modular study design. The challenge to the practitioner however is to know how the modular aspects of the study should be triggered on the basis of prior knowledge of a particular chemical, or on earlier fi ndings in the EOGRTS itself, requirements of specific regulatory frameworks not withstanding. Th e purpose of this document is to offer guidance on science-based triggers for these extended evaluations.