Scientific Program

Conference Series Ltd invites all the participants across the globe to attend 3rd International Summit on Toxicology & Applied Pharmacology Chicago, USA.

Day 1 :

  • Keynote Symposium
Location: Versailles - B

Session Introduction

Carter Cliff

Cellular Dynamics International, USA

Title: Pluripotent stem cell models-Application in toxicology and beyond

Time : 10:15-11:00

Speaker
Biography:

Carter Cliff has been a leader in the growth of several key technology platform companies in biotech. Over the past five years, he has helped to ensure the commercial success of Cellular Dynamics International (CDI), the premier manufacturer of human induced pluripotent stem cell products. Prior to that, he spent five years with Meso Scale Diagnostics implementing Pharma and academic adoption of multiplex immunoassay technologies. He also served as Scientific Consultant for Ingenuity Systems, the gold standard platform for modeling omics data, during their formative years from 2001-2004.

Abstract:

Induced pluripotent stem (iPS) cell technology off ers unprecedented opportunities to move beyond a “one size fi ts all” approach to pharmacology and toxicology, to a model where individual genetic and molecular profi les are used to guide diagnosis, drug development, and therapeutic decisions. Initially described in 2007, human iPS cells are derived from a patient’s somatic cells (e.g. blood, skin) and have the potential to diff erentiate into any cell type in the human body. In the last 5 years, a rapidly growing body of literature has emerged demonstrating the use of iPS cell-derived diff erentiated cells to demonstrate human relevant toxicity as well as recapitulate human disease phenotypes in vitro. Th ese novel human cell models are rapidly becoming the standard of choice for disease research and drug discovery as they off er better opportunities for therapeutic decision-making. Several case studies will be presented demonstrating how iPS cell-derived cardiomyocytes, neurons, and hepatocytes are being used today for drug development and discuss their potential future applications.

Break: Group Photo
Coffee Break 11:00-11:20 @ Versailles Foyer
  • Track 1: Clinical and Forensic Toxicology
    Track 2: Systems Toxicology
    Track 3: Mechanistic and Predictive Toxicology
Location: Versailles - B
Speaker

Chair

Anne Marie Vinggaard

Technical University of Denmark, Denmark

Speaker

Co-Chair

Arunabha Ray

University of Delhi, India

Speaker
Biography:

Brad L Urquhart obtained his PhD in 2006 in Pharmacology and Toxicology at Western University in London, Ontario. He completed Post-doctoral training at Vanderbilt University and Western University in Clinical Pharmacology. In 2009, he began as an independent Investigator at Western University. His lab focuses on changes in drug disposition in the setting of kidney disease.

Abstract:

Chronic kidney disease (CKD) is associated with a decreased expression and activity of several cytochrome P450 enzymes. This may result in drug-associated toxicity in CKD patients taking drugs that are metabolized by affected isozymes. The objective of this study was to determine the mechanism of hepatic drug metabolizing enzyme down-regulation in CKD. Hepatic CYP3A1, CYP3A2 and CYP2C11 mRNA expression were determined in rats with surgically induced CKD. Chromatin Immunoprecipitation (ChIP) was performed to determine nuclear receptor and epigenetic mediated differences in the promoter region of these enzymes. Hepatic CYP3A and CYP2C11 mRNA expression was significantly decreased in CKD rats compared to controls (P<0.05). RNA polymerase II binding to the CYP3A and CYP2C11 promoter regions was decreased in CKD rats (P<0.05). ChIP also revealed a decreased PXR binding to the CYP3A2 promoter in CKD rats (P<0.05). HNF4α binding to the CYP3A and CYP2C11 promoter regions was also decreased compared to controls (P<0.05). The decrease in PXR and HNF4α binding was concurrent with diminished histone 4 acetylation in the CYP3A2 promoter locus for nuclear receptor activation. The uremic toxin indoxyl sulfate also mediates a decrease in CYP3A expression. A novel mechanism of drug metabolizing enzyme regulation in CKD was demonstrated. The results show that decreased CYP3A and CYP2C11 mRNA expression is secondary to decreased PXR and HNF4α binding as a result of histone modulation in CKD. These data may partially explain why patients with CKD have a higher incidence of adverse medication events than patients with normal kidney function.

Mary L S Queiroz

State University of Campinas, Brasil

Title: Underlying mechanisms indicative of autoimmunity in silica-exposed workers

Time : 11:40-12:00

Speaker
Biography:

Mary L S Queiroz has completed her PhD from the University of Manchester, England, and her Postdoctoral studies from WEHI, Melbourne, Australia. She is a Full Professor, Director of the Laboratory of Immunopharmacology, Medical Faculty, UNICAMP, Campinas, Brazil. She has published more than 80 papers in reputed journals and presented several pioneer and original results in the literature. She worked as a World Health Organization (WHO) Temporary Advisor to the preparation of the International Programme on Chemical Safety (IPCS) Environmental Health Document Principles and Methods for Assessing Autoimmunity Associated with Exposure to Chemicals, organized by the United Nations Environment Programme (UNEP), the International Labour Organization (ILO) and the World Health Organization (WHO), through the International Programme on Chemical Safety (IPCS).

Abstract:

In the present study we investigated underlying mechanisms indicative of the presence of autoimmunity in workers exposed to silica (n=103). Original results were obtained with the quantification of interleukin-2 (IL-2), soluble IL-2 receptors (sIL-2R), Natural Killer (NK) cells and CD8+/CD4+ lymphocytes. Reduced levels of IL-2 and CD4+ cells were observed in the exposed population, in association to significant increases in the levels of sIL-2R, NK cells (CD16+ and CD56+ subpopulations) and T CD8+ cells. These findings are relevant in view of the fact that IL-2 is essential for natural tolerance and prevention of autoimmune diseases due to its involvement in the differentiation and function of T CD4+ lymphocytes. Moreover, NK cells are recognized by promoting tissue damage, induction of autoimmunity and development of fibrosis. In addition, sIL-2R receptors liberated in the circulation by activated T lymphocytes are used as biological markers of immune activation. The results we obtained in this area generated relevant information for the more precise conceptualization of autoimmune pathogenic processes whose origin is questionable.

Speaker
Biography:

Neelam Shrivastava had completed MBBS in 1988 from Indore University India and LLB from Bhopal University in 1999. She has worked in Public Health Department as Assistance Surgeon till 1996 and since last 18 years she is working as a Medical Officer in Medico Legal Institute, Gandhi Medical College, Bhopal, India. There, she has done more than 5000 autopsies of different nature and expert opinions. She has also presented two international papers i.e. one in Istanbul, Turkey and another one in Goa, India.

Abstract:

One of the ways adopted by person for suicide is drowning. Criminals also hide their crime by throwing person in water after murder. To identify antemortem drowning or postmortem drowning, many postmortem findings are considered along with diatom test from bone marrow but many fallacies are there and false results are obtained. To overcome all these difficulties, the new method is proposed which is easy, less cumbersome, economical and confirmatory test; drowning by diatom test from tracheal fluid obtained by distilled water washed tracheal fluid.

Speaker
Biography:

Arunabha Ray is MD, PhD from Faculty of Medicine, University of Delhi, with postdoctoral experience in Canada and the USA. He is Chair, Department of Pharmacology at the Vallabhbhai Patel Chest Institute, University of Delhi. He has more than 35 years teaching and research experience in basic and clinical pharmacology and toxicology and has been the recipient of several awards and honors for research excellence. He has more than 150 research publications, is author of several text and reference book chapters, editor of 04 books in his areas of expertise, and author of a Textbook in Pharmacology.

Abstract:

Theophylline (a methylxanthine), a potent bronchodilator, has reemerged as an important adjunct in the treatment of obstructive airway disease, but its narrow therapeutic index remains a persistent problem with the use of this drug. Neurobehavioral and cardiotoxicity are predominant adverse events after clinical use. Initial clinical studies to evaluate adverse drug reaction (ADR) profiles of patients of bronchial asthma and COPD who were prescribed theophylline showed that such therapy was associated ADRs like anxiety, palpitations, dyspepsia, muscle spasm, paresthesia, etc. Preclinical studies were then conducted to assess the mechanisms of theophylline-induced anxiety and tachycardia in experimental animals. Aminophylline dose dependently induced anxiety and tachycardia which were not attenuated by adenosine agonists or phosphodiesterase inhibitors. Interestingly, pretreatments with the antioxidants, ascorbic acid, α-tocopherol (alone or in combination) attenuated both anxiogenesis and tachycardia in separate sets of experiments. Aminophylline induced anxiety and tachycardia were associated with alterations in the biochemical markers of oxidative stress viz. elevations in MDA levels and reductions in GSH activity in blood and brain. Pretreatments with the antioxidants attenuated the methylxanthine induced changes in oxidative stress markers. Further, L-arginine (NO precursor) pretreatment also reversed aminophylline induced (a) anxiety and tachycardia and (b) brain and blood oxidative stress markers. These results indicate that oxidative stress could be involved in methylxanthine induced toxicity and antioxidants could act as possible antidotes in such situations. Such reverse pharmacology approach could also be effectively used to assess toxicodynamics of drugs with safety concerns and help in devising strategies to prevent them.

Dimple Damore

Bhavan’s Sheth R.A. College of Science, India

Title: Influence of melatonin on arsenic mediated pancreatic damage in Swiss albino mice

Time : 12:40-13:00

Speaker
Biography:

Dimple Damore has completed her PhD in Zoology (Toxicology) at Gujarat University, Ahmedabad, India in 2008. She is an Associate Professor in the Department of Zoology at Bhavan’s R.A.College of Science, Ahmedabad, India. Her area of interest is environmental toxicology.

Abstract:

Arsenic compounds are reported as environmental toxicants and human carcinogens. Exposure to arsenic imposes a big health issue worldwide. This study was conducted to evaluate the ameliorating effect of melatonin (MLT) on arsenic induced pancreatic damage in Swiss albino mice. Arsenic trioxide (As2O3) was administered orally at the dose of 0.5 and 1.0 mg/kg body weight and MLT was given intraperitoneally (10 mg/kg body weight) for 30 days. At the end of the experimental period, serum amylase, serum lipase, blood glucose, protein and total sulfhydryl groups were measured in addition to histological evaluation. The toxic effect of arsenic was indicated by increased serum amylase, serum lipase and blood glucose in a dose dependant manner. Arsenic intoxication also showed by decreased levels of protein and total sulfhydryl groups. In addition, arsenic exposed mice exhibited destruction of the exocrine and islet cells damage with degenerative changes. Simultaneous administration of MLT exhibited a significant reversal of arsenic-induced toxicity in pancreatic tissue. Furthermore, the histopathological studies confirmed the protective effect of MLT by reducing the pathological changes due to arsenic intoxication in pancreas. These results suggest that MLT has a potential protective effect over arsenic induced pancreatic dysfunction in Swiss albino mice.

Candace Su-Jung Tsai

Purdue University School of Health Science, USA

Title: Nanoparticle exposure assessment, Dose metric and controls

Time : 13:00-13:20

Speaker
Biography:

Tsai is an Assistant Professor at Purdue University; she served as a Research Manager for Nanotechnology Environmental Health and Safety in the Center for High-rate Nanomanufacturing at University of Massachusetts Lowell for 5 years after her doctorate. She is recognized as an expert in investigating nanoparticle exposure assessment and the engineering control techniques to be used for exposure elimination. She has published over 100 journal articles and conference papers related to her ground-breaking research since 2008. She is the executive officer of Nano Group in AIHA and has given numerous plenary presentations in various conferences.

Abstract:

Inhalation exposure to airborne nanoparticles (NPs) has been reported during manual activities using typical fume hoods and manufacturing processes, published by Tsai. This research studied potential inhalation exposure associated with the manual handling of NPs using two new nanoparticle-handling enclosures and two biological safety cabinets (BSC), and discussed the ability to contain NPs in the hoods to reduce environmental release and exposure. Airborne concentrations of 5 nm to 20 µm diameter particles were measured while handling nanoalumina particles in various ventilated enclosures. Tests were conducted using two handling conditions and concentrations were measured using real-time particle counters, and particles were characterized and collected on TEM grids to determine particle morphology and elemental composition. Airflow patterns were characterized visually using a laser light sheet and fog. The average number concentration increase at breathing zone outside the enclosure was less than 1400 particle/cm3 for each particle size at all tested conditions and the estimated overall mass concentration was about 83 µg/m3, which was less than the dosage of typical nanoparticle inhalation exposure studies. The current occupational exposure limits (OELs) to nanoparticles were under development with few was recommended by NIOSH. The current status of developing strategy for setting OELs discussed that the dose metric needs to be harmonized for exposure assessment and toxicological studies. The challenge of current efforts is to further investigate occupational exposure and the associated biological responses.

Break: Lunch Break 13:20-14:00 @ Monaco Grand Ballroom
  • Track 4: Pediatric Toxicology
    Track 5: Toxicology and Applied Pharmacology
Speaker

Chair

Hemant Misra

Prolong Pharmaceuticals, USA

Speaker

Co-Chair

Sharda Shah Peshin

All India Institute of Medical Sciences, India

Session Introduction

Hemant Misra

Prolong Pharmaceuticals, USA

Title: Designing clinical interference studies to address colorimetric assays

Time : 14:00-14:20

Speaker
Biography:

Hemant Misra received his PhD from Lucknow University in Medicinal and Pharmaceutical Chemistry and has published over 55 articles and a patent. He is VP Clinical Development for Prolong Pharmaceuticals. He has over 30 years of biopharmaceutical development, global clinical study management and corporate development experience. He has managed drug development, CGMP manufacturing, CTM, quality systems and multiple global clinical trials.

Abstract:

The development of a drug product, SANGUINATE™ (pegylated carboxyhemoglobin bovine) with a hemoglobin molecule (Hb) as a component, creates challenges in accurately measuring clinical chemistry analytes in human and animal samples. Most clinical analytes are assayed using spectroscopic methods employing calorimetric analysis. Therefore to ensure that the results from both preclinical and clinical safety studies are accurate, it is necessary to design and execute interference studies to determine what analytes are affected by the presence of Hb from SANGUINATE and what correction factors can be used to permit accurate measurements during preclinical and clinical studies. To this end, a series of studies was designed using three animal species as well as blood samples from normal human volunteers. The study design included the use of four different methods: clinical chemistry, hematology, coagulation and blood gas analysis using different instrumentation. The various instruments employed spectroscopic analysis, tonometry, radiometry and nephelometry. Immunologic analysis included an ELISA- based system. Using the data generated from these studies, correction factors were determined for most analytes. The results from the multispecies study demonstrated species equivalence. In general, there were very few differences among the species. Any differences were adjusted for by using species-specific correction factors. The first indication for SANGUINATE is Sickle Cell Disease which has both an ischemic and hemolytic component. Challenges still remain to measure interference in patient’s samples with active hemolysis. In addition, the variety of instrumentation used in hospitals will require approaches to ensure that data generated is accurate and correlated.

Speaker
Biography:

Gilles Hanton graduated as Doctor in Veterinary Medicine in 1976 and as Diplomate of the American Board of Toxicology in 1991. He has worked for more than 26 years in the Departments of Toxicology of Searle, Pfizer and Tibotec/Johnson & Johnson. He has a large practice of conducting regulatory and mechanistic toxicity studies and he has acquired a broad experience in the development of new molecules and in safety assessment of pharmaceutical compounds. He has developed an expertise in cardiovascular toxicology and pharmacology and in inhalation toxicology. He is currently working as a Consultant for the Pharmaceutical and Biotechnology Industry.

Abstract:

Echocardiography (EC) is a method used for investigating cardiac morphology and function. Two-dimensional EC gives a visualization of the morphology of the heart. M-mode EC allows heart function to be monitored. Pulsed Doppler EC is the method of choice for measuring blood flows through valves and large vessels. EC is used in routine in clinic and veterinary practice but is infrequently applied to preclinical evaluation of drug toxicity and safety pharmacology despite a number of advantages. Since similar investigations can be done in laboratory animals and humans, preclinical and clinical findings can easily be transposed to each other. EC is totally non invasive, it does not induce any suffering to the animals and has no impact on health and physiology. It allows repeated measurements and consequently monitoring of development and evolution of adverse effects. In this way, EC evaluates the functional adverse effects of drugs on the cardiovascular system and the consequences of induced lesions. Moreover, using the different modes of EC it is possible to determine the changes in heart contractility and hemodynamics that are involved in the development of cardiovascular lesions. This is illustrated by an experiment in dogs treated with minoxidil. The development of lesions in the right atrium and left ventricle were considered to be related to changes in the function of these cardiac structures as demonstrated by EC recordings. These findings confirm the usefulness of EC in assessing the pathogenesis of drug-related cardiac toxicity.

Speaker
Biography:

Agnieszka Potęga obtained her Ph.D. in 2011 in chemical sciences (biotechnology) at the Gdańsk University of Technology (Poland) where she is currently working in the Department of Pharmaceutical Technology and Biochemistry . Her area of research interests are studies on the role of activation and detoxification metabolism in the mechanisms of action and biological outcome of potential anticancer agents and mechanisms of inhibition of drug-metabolising enzymes activity. In particular, her academic work is focused on generation conditions and identification of reactive intermediates from model antitumor acridinone derivatives.

Abstract:

The knowledge of the metabolic pathways and the biotransformation of new drugs in the human body is one of the major challenges in pharmaceutical research. It is crucial for elucidation of degradation routes of the new biologically active compounds, especially in the area of possible toxicity. Conventional in vitro drug metabolism studies are based on incubating drug candidate with e.g. hepatocytes or, most importantly, liver cell microsomes and isolating and detecting the metabolic products. Microsomes contain a high enzyme concentration of the cytochrome P450 (CYP) superfamily, which catalyses the majority of oxidative metabolism reactions. As a purely instrumental alternative to mimic drug oxidation reactions occurring in the human body the electrochemical simulation has been developed. Electrochemistry (EC) is recently gaining more attention as a tool in rapid, on-line single compound screening. Potential oxidative metabolites are generated in an electrochemical cell and are subsequently identified by on-line mass spectrometry (EC/MS). C-1311 (5-diethylaminoethylamino-8-hydroxyimidazoacridinone, SymadexTM) is representative antitumor imidazoacridinone derivative developed in our laboratory. It exhibits high cytotoxic activity against a broad spectrum cell lines in vitro and of transplantable animal tumors. The previous studies on molecular mechanisms of its biochemical action showed that the metabolic activation by intracellular enzymes might be necessary for the following interactions of this agent with cell proteins and DNA. Next, we showed that compound was metabolized by enzymes originating from rat and human liver microsomes (RLMs and HLMs). In the presented work C-1311 was chosen as model drug to investigate oxidative metabolism using electrochemistry (the ROXYTM EC System, Antec, USA) coupled to mass spectrometry. The results obtained by EC were then compared with conventional in vitro studies with RLMs as well as HLMs. Electrochemical conversion of C-1311 into phase I metabolites was successfully achieved. Comparing MS results from liver cell microsome incubations to MS results from electrochemical studies we were able to demonstrate that two main metabolic products of C-1311 (side chain degradation products) were detected both in the conventional microsomal approach and in the electrochemical simulation. Thus, it can be noted that EC is very well-suited for the simulation of the oxidative metabolism of imidazoacridinone derivative. In summary, our study clearly confirms that EC/MS method is a feasible alternative to microsomal studies. It can be a versatile and userfriendly tool in drug discovery and development when applied complementary to established in vitro or in vivo approaches.

Sarathchandra Ghadevaru

Tamil Nadu Veterinary and Animal Sciences University

Title: Veterinary pharmacovigilance survey conducted in Tamil Nadu state, India – A status report

Time : 15:00-15:20

Speaker
Biography:

Sarathchandra Ghadevaru is the Professor & Head, Pharmacovigilance Laboratory for Animal Feed and Food Safety in the Directorate of Centre for Animal Health Studies, Tamil Nadu Veterinary and Animal Sciences University, Chennai-51. He is a Veterinary Pharmacology and Toxicologist having 25 years of experience in the field of Veterinary Pharmacology and Toxicology. He obtained Ph.D., (Environmental Toxicology), University of Madras in 1997. His area of specialization is Veterinary Diagnostic and Regulatory Toxicology. His doctoral programme elicited the toxicodynamics/ mode of action and antidotes to combat one of the common suicidal and homicidal phytotoxin (Cleistanthus collinus (oduvan thalai: Tamil) very frequently encountered in malicious poisoning of cattle. The growing resonance in reduction of animals for toxicity evaluation (alternatives to animal toxicity testing), the findings of the phytotoxin were evaluated in two invitro system namely vero cell line and chick embryo as suitable model for alternative to animal toxicity. His mission is to create awareness to livestock farmer regarding residue free livestock products towards Global Food Security

Abstract:

Veterinary pharmacovigilance monitors the safety of veterinary medicines, including vaccines (VAC) used for the prophylaxis, diagnosis or treatment of diseases in animals once they reach the market after authorization. In India, there is no present government policy to survey and evaluate adverse drug events (ADEs) / Pharmacovigilance programme for veterinary medicines. Therefore, essential information such as frequency, severity of treated animal ADEs and reliable data about frequent ADE-producing drugs remains unknown. The objective of the study was to assess and communicate risks and benefits in the market ultimately to educate the veterinarians and the stake holders on the safety and efficacy of veterinary drugs and biologicals. A 12-month period pilot study was conducted to monitor the ADE for frequently used drugs (labeled/extra labeled drugs). A survey protocol consisting of a questionnaire about used drugs in livestock was developed; the questionnaire was distributed to 300 veterinarians of Tamil Nadu state. The veterinarians were instructed to voluntarily report on the various types of drugs used and the ADEs, if any observed. More than 37% ADEs were related to antimicrobials, antiparasitic and anti-inflammatory agents. A further 27% of ADEs were due to vitamins and feed additives. Two cases of ADEs were observed in FMD vaccination, in cattle and canine Parvo vaccine in dogs. In poultry, tiamulin and salinomycin ADEs induced serious mortality. The present study warrants for the need of sustained veterinary pharmacovigilance programmes in livestock for timely ADEs presenting drug detections and drug safety improvement.

Speaker
Biography:

De-Qun Sun has completed her Master and PhD from the Peking University and the Beijing Institute of Chemistry, Chinese Academy of Sciences respectively. After finishing the work contract as division head in Roche-Basilea, China R&D novel drug centre, she returned to K.U. Leuven as post-doctor to continue the research in drug design. From 2006, she became the professor in field of medicinal chemistry in Shandong university, China. Up to now, her research was focused on drug design and development and she has published more than 30 papers in international journals.

Abstract:

Schistosomiasis is a relatively neglected tropical disease and it has long been a major public health problem in China and other subtropical countries. Reported by WHO, of the five species of schistosome, schistosomiasis caused by S. japonicum leads to more serious health damages and it is the most difficult one to be prevented. Not only does S. japonicum have an obvious difference on ecology and biology with other schistosomes, but also it has more complex transmission links and epidemic factors. Over the past decades, chemotherapy is the main strategy of schistosomiasis control. Praziquantel (PZQ) is currently the first choice of drug for treatment of Schistosoma mansoni and Schistosoma haematobium infection and is the only drug for treatment of S. japonicum infection. However, PZQ-resistance has been confirmed, therapeutic dose in China mainland has been increased from 40 mg/kg/one time to 60 mg/kg/two times currently. Especially, deficiency of praziquantel (PZQ) due to its low efficiency to juvenile stages of schistosome caused the endless of Schistosomiasis. The Schistosomiasis will never disappear even after PZQ has been used in clinic for almost 40 years. In present study, three praziquantel analogues with asymmetric cycle were synthesized for biological antischistosomal tests. Compound 2 was developed as drug lead for its excellent activity against juvenile stages of S. japonicum both in vitro and in vivo on mice and rabbits with low cytotoxicity and no drug resistance, which could be a good drug candidate to make up the deficiency of PZQ and benefit PZQ action mechanism elucidation.

Speaker
Biography:

Huijun Sun is the Professor of Pharmacology of Dalian Medical University, China. Her major is pharmacology of metabolic diseases, such as hyperlipidemia, atherosclerosis and osteoporosis and she has published more than 50 papers in reputed journals. She completed her Ph.D in Dalian Medical University, China and have ever studied and worked in the University of Tsukuba, University of Yamanashi of Japan.

Abstract:

Recently, increasing studies indicated the relationship between oxidative stress and osteoporosis. And some studies have been done to detect the possible beneficial effects of Alpha-lipoic acid (ALA), a potent antioxidant, on osteoporosis in vivo and in vitro. However, the detailed mechanism(s) underlying the bone-protective action of ALA are still poorly understood. The present study aims to examine the mechanisms by which ALA produces bone-protective effects in vitro and in vivo on base of its antioxidant effects, thus the effects of ALA on H2O2-treated MC3T3-E1 pre-osteoblasts and ovariectomized osteoporosis rat model were investigated by using bone biomechanical testing, microcomputed tomography, western blotting and qRT-PCR analysis. The results showed that ALA promoted osteoblastic formation, inhibited osteoblastic apoptosis, increased OPG/RANKL ratio and enhanced bone formation in vitro and prevented bone loss in vivo. And the effects of ALA were via modulating Nox4/ROS/NF-κB and Wnt/Lrp5/β-catenin signaling pathways, which revealed possible mechanisms of bone-protective effects of ALA. The current study indicated that ALA might be a candidate for the prevention and therapy of osteoporosis clinically at the end of advanced studies.

Break: Coffee Break 16:00-16:20 @ Versailles Foyer
Speaker
Biography:

Jianyong Li professor has completed his Ph.D at the age of 34 years from the Graduate School of Chinese Academy of Science (CAS) and postdoctoral studies from the Graduate School of Chinese Academy of Agricultural Science (CAAS). He is leader of research and development program for veterinary chemical pharmaceutical at Agricultural Science and Technology Innovative Program of CAAS. He has published more than 190 scientific papers, of which English language papers were more than twenty.

Abstract:

Aspirin eugenol ester (AEE) is a promising drug candidate for treatment of inflammation, pain and fever and prevention of cardiovascular diseases with fewer side effects than its precursor, aspirin. Investigation on its metabolic process in target animal species will help to illustrate its action mechanism and to establish its residual mark compound to formulate its dosage. Six beagle dogs were orally given a dose of 20mg•kg-1 of AEE and one dog was used to prepare blank liver microsomes. Their liver microsomes were prepared for in vitro study and their plasma and urine were collected for in vivo metabolic analysis using liquid chromatography tandem mass spectrometry (HPLC-MS/MS). In this study we identified 10 metabolites, M1, M2, M3, M4, M5 in phase I and M6, M7, M8, M9, M10 in phase II.

Li XIA

Shanghai 6th People’s Hospital, China

Title: Cochlear cell death induced via cisplatin or gentamycin in combination with furosemide in rodents

Time : 16:40-17:00

Speaker
Biography:

Li Xia has been engaged in otology for nearly 10 years. Now he is working as a senior researcher as well as a clinical doctor in the Dept. of Otorhinolaryngology of Shanghai 6th People’s Hospital. He has published 4 papers in reputed international journals. He has extensive experience in ototoxic research. In particular, he mainly worked on the drug-induced ototoxicity. He solved many issues about the ototoxic model establishment in laboratory, which could facilitate the researches of neural function and the therapies against ototoxicity. He is pleased to share his knowledge and skills with fellow researchers.

Abstract:

Ototoxic models of animal represent an elemental tool in basic otological research. In the present study, using guinea pigs we compared cochlear lesions mediated via cisplatin applied in terms of two regimens: Consecutive application alone and in combination with furosemide. The influences of furosemide alone were also assessed; it was observed to result in temporary hearing loss and reversible damage to the stria vascularis. Consecutive administration of cisplatin alone tended to be disadvantageous because it bred progressive body weight loss and higher mortality compared with the combined regimen, which utilized a smaller cisplatin dose. The combined regimen brought about remarkable hair cell loss without corresponding lesion of spiral ganglion neurons (SGNs). This difference suggests that the co-administered regimen did not mimic the damage to cochlear neuronal innervation caused by clinical application of cisplatin. In the meantime, we spread this method to the ototoxic model build in mice. Co-administration of gentamicin and furosemide caused marked hair cell loss as well as less mortality compared with consecutive application of gentamicin in mice. Due to different pharmacokinetics between cisplatin in guinea pigs and gentamicin in mice, the injection regimens of co-administration of furosemide-cisplatin in guinea pigs and gentamicin-furosemide in mice varied. Overall, the methods of co-administration of cisplatin/gentacimin and furosemide in rodents facilitate ototoxic model build.

Speaker
Biography:

Begum Rokeya has completed her Ph.D in Pharmacology at the age of 28 years from Kyev Institute of Pharmacology and Toxicology, Ukraine. She is serving as Professor and Chief Research Officer in the Dept of Pharmacology, in Bangladesh Institute of Research and Rehabilitation in Diaebetes, Endocrine and Metabolic Disorder (BIRDEM), a WHO collaborative Center for Research on Prevention and Control of Diabetes. She has published more than 50 papers in the peer-reviewed national and international journals & chapters in Books (3).

Abstract:

Global assessment reveals that, for the foreseeable future, the majority of the people of the developing countries will have to depend on herbal medicine for their primary healthcare as modern medicine will not be accessible to them. Though herbal medicines are considered safe due to their age-old usage, but serious adverse effects have been reported for herbal medicines. Therefore, assessment of safety and quality of herbal products is a necessity. This study evaluated the anti-diabetic properties and made a preliminary assessment of the concentrations of some of the most common toxic metals in six anti-diabetic herbal preparations (ADHPs) available in Bangladesh. ADHP (1 to 6) were collected from herbal medicine shops produced in five different local herbal pharmaceuticals. Acute anti-diabetic study was done on STZ induced diabetic model rats with a single feeding. Then two of the herbal preparations were fed for 28 consecutive days with different doses. Simultaneously the concentrations of the most common toxic metals i.e., Pb, Cu, Mn, Cd and As were determined by AAS in the ADHPs. The results showed that among the six ADHPs only one (ADHP-3) was found to be effective as anti-diabetic. Regarding the toxic metals the level of As in all ADHPs has been found to be below Maximum Acceptable Limit (MAL) of nutritional supplement intake whereas concentration of Pd, Cu and Mn in ADHP-1 and Cu, Mn in ADHP-6 were high of MAL of nutritional supplement intake/day. The observations call for extended evaluation of all herbal products for their safety.

Speaker
Biography:

Hemant Misra received his PhD from Lucknow University in Medicinal and Pharmaceutical Chemistry and has published over 55 articles and a patent. He is VP Clinical Development for Prolong Pharmaceuticals. He has over 30 years of biopharmaceutical development, global clinical study management and corporate development experience. He has managed drug development, CGMP manufacturing, CTM, quality systems and multiple global clinical trials.

Abstract:

SANGUINATE™ (pegylated carboxyhemoglobin bovine) is a dual carbon monoxide and oxygen delivery agent that has potential use for indications whose pathophysiology includes an ischemic or hemolytic component. While SANGUINATE is initially under clinical development as an acute therapeutic candidate, it has the potential to be used chronically. Designing toxicology studies must not only deal with the potential safety issues of using bovine hemoglobin but the potential use of this product for both acute and chronic administration. Therefore, toxicology studies were designed both to thoroughly address the potential of vasoreactivity in addition to traditional safety pharmacology studies. To address any toxicity concerns of its use as a single or repeating dose therapeutic, SANGUINATE was tested in multiple species as a single agent, in repeating doses, and as with any new investigational drug, at ascending dose levels to determine its maximum tolerated dose. Twelve toxicology studies were performed in 4 species. Renal toxicity was assessed and no abnormal clinical observations were observed with regards to renal glomerular filtration rate and renal blood flow. There were no adverse effects identified for any dose and therefore, a no observed adverse effects level could not be determined not even at dosage levels of 1200 mg/kg (monkey), 1600 mg/kg (pig) and 2400 mg/kg (rat). The dose limitation of SANGUINATE appears to be caused by plasma expansion of the administered dose, not actually by the activity of the product. This toxicology study design addressed FDA concerns and permitted SANGUINATE to move into clinical trials.

Speaker
Biography:

Friday EUboh completed his Ph.D at the age of 35 from University of Calabar, Calabar, Nigeria, and is presently an Associate Professor of Biochemistry, with Toxicology as his area of research interest. He served as the acting Head of Biochemistry Department in the Department of Biochemistry University of Calabar, Calabar, Nigeria, from 2011 to 2013. Dr. Uboh is a member of Nigerian Society of Biochemistry and Molecular Biology, and Institute of Public Analysts of Nigeria. He has more than 60 papers published in reputable Journals, and is a reviewer and editorial board member of many Journals of repute. He has also presented many conference papers, locally and internationally.

Abstract:

Nitrocellulose thinner (NCT) is one of the commonly used industrial chemical solvents. Oral exposure to NCT has been reported to cause nephrotoxicity in rat. The levels of such serum biochemical indices as creatinine, urea, uric acid and electrolytes (Na+, K+, HCO3- and Cl-) are useful in assessing the functional integrity of renal tissues.This study assessed the effect of combined administration of vitamins C (VitC) and E (VitE)on serum creatinine, urea, uric acid, Na+, K+, HCO3- and Cl- in male rats orally exposed, once daily, to 40.0mg/kg body weight of NCT, for 28 days. Nine groups, of six male rats each, were administered with distilled water, vegetable oil, VitC only, VitE only, VitC + VitE,NCT only, NCT + VitC, NCT + VitE, and NCT + VitC + VitE, respectively, for 28 days. On the 29th day of the experiment, the rats in each group were sacrificed and blood samples collected for serum creatinine, urea, uric acid, Na+, K+ and Cl-analyses. The results showed that exposure to NCTfor 28 days caused a significant (P<0.05) increase in serum creatinine, urea, uric acid, K+ and Cl- levels, and decrease in Na+ levels compared to the control. Administration of vitC and vitE singly, or in combination, did not cause any significant (p>0.05) difference in the level of these indices, compared to control. However, the serum creatinine, urea, uric acid, K+ and Cl- levels obtain for rats treated with NCT + VitC, NCT + VitE and NCT + VitC + VitE were significantly(p<0.05) lower, while Na+ was higher, compared respectively with the levels recorded for rats given NCT only. Interestingly, the levels of these indices recorded for rats given NCT + VitC, NCT + VitE and NCT + VitC + VitE were within the same range as the levels recorded for the control group, with the levels for NCT + VitC + VitE group being closest to the control. The results of these serum indices correlated with the results of tissue histological assessment. From these results, it may be concluded that the nephroprotective potency of combined administration of vitamins C and E is higher than that of individual administration.

Speaker
Biography:

Isaac Julius Asiedu-Gyekye obtained his PhD inPharmaceutical Sciences specializing in Pharmacology and Toxicology in 1998 from Pyatigorsk State Pharmaceutical Academy. He is currently the Vice Dean of University of Ghana School of Pharmacy, the premier University in Ghana and Heads the Department of Pharmacology and Toxicology under the College of Health Sciences.Dr. Asiedu-Gyekye has acquired wide range of experience in the area of research into non-communicable diseases and natural products. He has also served on important Boards and Committees at the University. He is a member of the Technical Advisory Committee of the National Centre for Pharmacovigilance as expert in Pharmacology and Toxicology. He has made presentations in both local and International Conferences and has over 40 peer-reviewed publications in reputed journals and 2 books to his credit including a manual of harmonized procedures for assessing the safety and efficacy of plant medicines in Ghana.

Abstract:

Background: Polyhexamethylene guanidine (PHMGH) and polyhexamethylenebiguanide (PHMB) are antiseptics with antiviral and antibacterial propertiesof multipurpose use worldwide and also for treating pool water. Safety concerns have been raised by regulatory authorities about the use of these products for treatment of raw water to make it potable. This non-GLP preliminary study aims at investigating in a subchronic toxicity study possible effects at supra-optimal doses of these biocides. Methods: Both acute and 90- day subchronic toxicity studies of using 0.006 mg/kg, 0.012 mg/kg and 0.036 mg/kg PHMGH and 2 mg/kg, 8 mg/kg, 32 mg/kg and 40 mg/kg PHMB in Sprague-Dawley rats were administered orally. Haematological, biochemical and histopathological studies were conducted in both the acute and subchronic Toxicity studies. Results: LD50 for PHMGH and PHMB were estimated to be 600 mg/kg (ie LC50 2ml of 7.5% solution) and 16 mg/kg (LC50 1.6 ml of 0.4%) respectively when administered as a single dose by gavage via a stomach tube in accordance with the expected route of administration. The median lethal doses (LD50) were both accompanied by signs of neurotoxicity. Haematological and biochemical parameters in subchronic toxicity studies were non-significantin both the PHMGH and PHMB treated animals as compared to the controls which received deionized water. 20% of the animals at different doses showed various degrees of hydropic changes in proximal tubules while 10% of animals had theirliver tissues showing local areas of mild pericentral hepatocytes degeneration. PHMGH and PHMB did not produce any major organ defect with regard to the kidney, heart, and liver. Conclusion: The recommended residual concentrations of both PHMGH and PHMB after water treatment as well as their recommended doses for water treatment are far below the LD50. These results could serve as basis for investigating the full toxicological profile of these biocides and also for the treatment of raw water to make it potable.

Speaker
Biography:

Gilles Hanton graduated as Doctor in Veterinary Medicine in 1976 and as Diplomate of the American Board of Toxicology in 1991. He has worked for more than 26 years in the Departments of Toxicology of Searle, Pfizer and Tibotec/Johnson & Johnson. He has a large practice of conducting regulatory and mechanistic toxicity studies and he has acquired a broad experience in the development of new molecules and in safety assessment of pharmaceutical compounds. He has developed an expertise in cardiovascular toxicology and pharmacology and in inhalation toxicology. He is currently working as a Consultant for the Pharmaceutical and Biotechnology Industry.

Abstract:

Cardiac arrhythmias, in particular life-threatening Torsades de Pointes (TdP) are serious adverse effects associated with a number of pharmaceuticals belonging to different classes. It is therefore critical to have reliable biomarkers for assessing this risk during pre-clinical testing of new compounds. Prolongation of cardiac action potential and consequently of the QT interval of the ECG is generally considered as indicative of a risk of arrhythmia. Evaluation of drug effects on QT in preclinical studies is therefore requested by ICH guidelines (S7B). However there is now growing evidence that the prolongation of mean QT interval is not an accurate indicator of the risk of arrhythmia and that other parameters of cardiac repolarisation are more predictive. They include instability of action potential duration and increase in transmural heterogeneity of myocardial repolarisation (spatial variability), which can be investigated in specific in vitro tests. We have evaluated the ECG correlates of both markers in studies testing the effects of isoproterenol, astemizole and hypokalaemia, which are known to be associated with a proarrhythmic risk. Instability of action potential duration is associated with an increase in the beat-to-beat (temporal) variability of the QT interval that is evaluated by calculating the coefficient of variation of this parameter or by plotting QT from each beat vs. QT of previous beat. Spatial variability of repolarisation correlates with changes in the morphology of the T wave, in particular increase in the interval between the peak and the end of the T wave and notching of this wave.

Sharda Shah Peshin

All India Institute of Medical Sciences, India

Title: Poisoning in children: A poisoning helpline experience

Time : 18:40-19:00

Speaker
Biography:

Sharda Shah Peshin’s area of interest is Toxicology and Poisoning. She has a number of research publications in toxicology and poisoning including research papers, books, manuals, brochures and management cards. She has also published a number of educative leaflets, posters and handouts to raise awareness about the safe use of chemicals and prevention of poisoning. This literature is of immense help to hospitals, primary health centers and general public. She was a member of the Protocol Development Group of the National Snakebite Management Protocol India, Directorate General of Health Services, Ministry of Health & Family Welfare, Govt. of India, 2008.

Abstract:

Children are exposed to a wide range of toxic products with spectrum getting broadened due to introduction of a diverse range of pesticides, household cleaners, drugs etc from time to time. Easy availability of poisonous pesticides in a largely agrarian economy coupled with lack of awareness about the safe use, access control, early symptoms and first responder mitigation strategies add to the problem. The data from India is essentially based on hospital studies and hence the exact magnitude of the problem cannot be defined .The present study based on telephone calls made to the National Poisons Information Centre, was aimed to determine the age groups in children involved and the common products implicated in poisoning over a period of five years (March 2009-April2014). The calls were divided into four age groups (Gp.I: 0-6yrs., Gp.II: >6-12yrs., Gp.III : >12-16yrs., Gp.IV :> 16-18 yrs.). The substances implicated were categorized into eight groups of household products, agricultural pesticides, industrial chemicals, drugs, bites and stings, plants, unknown and miscellaneous classes. The mode of poisoning was predominantly accidental and the age group mainly involved was Gp.I. Males outnumbered females. The highest incidence was due to household products comprising of pesticides, disinfectants, detergents and corrosives, antiseptics etc. The incidence and trend could be variable due to lack of coordination and harmonization of reporting and the absence of a central registry of poisoning cases. However, the study does highlight the increasing use of household products. Since pediatric poisonings are largely due to negligence and ignorance, implementation of prevention programmes and identification of high risk circumstances can help in reducing morbidity and mortality in children.

Speaker
Biography:

Saganuwan Alhaji Saganuwan is a senior Lecturer and the Acting Head Department of Veterinary Physiology, Pharmacology and Biochemistry, University of Agriculture, Makurdi. He has over 40 scientific papers mostly published in international journals of high repute and a few presented at national and international conferences. He is a renowned scholar in the fields of Ethnopharmacology, Toxicology, Anesthesiology, Malariology, Pharmacokinetics, Translational Medicine, Veterinary Medicine, Pharmaceutical Calculation, Clinical Research, Drug Development and Science Education. He is an Associate Editor for Journal of Medical and Pharmaceutical Sciences, Editorial Board Member Research in Pharmaceutical Biotechnology, Journal of Infectious Diseases and Immunity, Journal of Diabetes and Endocrinology, International Journal of Pharmaceutical Biotechnology, Journal of Microbiology and Antimicrobials, and Technical Editor British Journal of Pharmacology. His profile is in the Encyclopaedia of Who is Who in Nigeria. He is a Faculty member at the University of Agriculture, Makurdi. He holds Doctor of Veterinary Medicine (DVM), MSc and PhD in Pharmacology from the Usmanu Danfodiyo University, Sokoto, PGD in Statistics and PGDE in Science Education from the University of Agriculture, Makurdi respectively. He is a licensed member of Veterinary Council of Nigeria, member of Nigerian Institute of Food Science and Technology, Science and Technology Forum, Nigerian Society for Indigenous Knowledge and Development, Nigerian Veterinary Medical Association and Nigerian Academic Staff Union of Universities.

Abstract:

Allometric scaling is an empirical examination of the relationships between the pharmacokinetic parameters and body size. Piroxicam is a benzothiazine compound possessing an enolic 4-hydroxy substituent. It is anti-inflammatory, antipyretic and analgesic drug, 99% plasma protein bound with active enterohepatic circulation and prolonged half-life (30 – 85 hours). The empirical oral therapeutic doses of piroxicam in cat and dog are 0.26 mg/kg and 0.3 mg/kg body weight respectively. Therefore human equivalent dose formula (HED) which is equal to animal dose (AD) multiplied by animal km divided by human km was used to project the therapeutic doses of piroxicam in dog, cat, monkey, baboon, rabbit, micro-pig, mini-pig, guinea-pig, hamster, squirrel monkey, marmoset, ferret, rat and mouse using 20 mg of piroxicam for average adult-human (70kg). Km is body weight (BW) divided by body surface area (BSA). The canonical findings reveal that oral therapeutic doses of piroxicam in dog (0.53 mg/kg), cat (0.56 mg/kg), baboon (0.53 mg/kg), micro-pig (0.30 mg/kg) and mini-pig (0.30 mg/kg) confirm the paradox of human equivalent dose formula (HED) bearing in mind the 0.29 – 0.58 mg/kg body weight of human. However the calculated higher therapeutic doses in monkey (0.85 mg/kg) and rabbit (0.89 mg/kg) may connote faster rate of elimination of piroxicam in these animals. Nevertheless, the very-high therapeutic doses of piroxicam in ferret (1.53 mg/kg), rat (1.7 mg/kg), guinea-pig (1.8 mg/kg), marmoset (1.84 mg/kg), squirrel monkey (1.59 mg/kg), harmster (2.6 mg/kg) and mouse (3.6 mg/kg), may denote high level of complexity in both pharmacokinetic and pharmacodynamics handling of piroxicam in these animals that are used for basic research. In conclusion, all the extrapolated doses can be administered orally per day then every 2 days in dog, cat, baboon, micro-pig and mini-pig until therapeutic response is achieved. In monkey and rabbit the extrapolated doses can be administered per day then every 3 days whereas in ferret, marmoset, squirrel monkey and laboratory rodents, the extrapolated doses can be administered per day then every 4 – 5 days interval. But when any of the following signs (anorexia, melena and vomiting) is observed, piroxicam should be withdrawn immediately.

Break: 18:30-19:30 Cocktails Sponsored by Journal of Clinical Toxicology @ Athens