8^th World Congress on Pharmacology and Toxicology July 24-25, 2017 Melbourne, Australia

Biography:

Belamy B Cheung was graduated from Sun Yat-sen University of Medical Science, Guangzhou, China and obtained her PhD degree at University of New South Wales, Australia. Presently, she is the Manager and Project Leader of the Molecular Carcinogenesis Program at Children's Cancer Institute Australia. Her research is currently focusing on drug discovery leading to the identification of small molecule inhibitors of oncogene targets. Most of her publications are in highly ranked journals, including Nature Reviews Cancer (IF37.9), Science Translational Medicine (IF15.8), Oncogene (IF 8.5) and Journal of the National Cancer Institute (IF14.3).

Abstract:

Embryonic cancer arises from postnatal persistent embryonal remnant or rest cells that are uniquely characterized by the absence of p53 mutations. We have showed that c-Myc and Myc N-overexpressing perinatal murine pre-B lymphocytes are resistant to apoptosis induced by interleukin-7 (IL-7) withdrawal and are associated with decreased p53 induction. From an initial library of 40,000 compounds, we generated a list of 56 hit compounds that displayed activity against Myc N-expressing pre-B cells in the absence of IL-7, but had minimal effect on cells in the presence of trophic factor. One of the lead compound, PB-798, reduced ganglia cell growth only in the absence of NGF and restored sensitivity to NGF withdrawal-induced cell death in myc N-expressing ganglia cells from TH-myc N homozygous mice, suggest that PB-798 can restore death sensitivity to trophic withdrawal in Myc-driven persistent rest cells. Furthermore, we investigated the potential mechanisms of cell death initiated by PB-798. By western blot, we found PB-798 treatment after 72 hours at 10 µM significantly reduced myc N protein levels in myc N-expressing clone F cells. We performed Affymetrix gene arrays and nanostring analysis to investigate the key genes/signaling pathways involved in the mechanism of cell death. We found that seven signaling pathways were significantly enriched. We have now identified 7 target genes in steroid biosynthesis and 5 target genes in JAK/STAT signaling pathways as the potential molecular targets for PB-798 drug action. Importantly, we have tested the efficacy of PB-798 in Myc N over-expression zebrafish neuroblastoma model and found that PB-798 significantly inhibits myc N-induced neuroblastic hyperplasia in the inter-renal gland (IRG) of this Myc N over-expression zebrafish model. PB-798 will be further tested in in vivo models of myc-driven tumor initiation such as the Eµ-Myc mouse model of lymphoma and the TH-myc N neuroblastoma mouse model.

Biography:

Abstract:

The use and popularity of complementary and alternative medicine (CAM) has sharply risen over the decades particularly in the United States. This includes herbal medications and practicing yoga, ayurvedic medicine, acupuncture and various others. It is postulated that there are several reasons including cost, perceived data, enhanced effects and non-regulated. Many medical schools are now introducing this into their curriculum to raise awareness.

CAM is not FDA approved and the complete active ingredients are unknown as is the pharmacokinetic disposition and mechanism of action. Literature speculates on the mechanism of action. Chronic use particularly in geriatric patients and with prescribed medications poses risks, side effects and potential interactions some of which are known. This may be exacerbated in patients with hepatic and renal compromise. Contraindications and use in pregnancy and pediatric patients is unclear.

Some potential concerns and side effects are the serotonin syndrome, induction of the CYP450 system, bleeding and gastrointestinal disorders and rhabdomylosis. This also extends to potential interactions with prescribed medication and attenuation of side effects.

This presentation focusses on commonly utilized herbal medications and potential side effects and interactions.

Biography:

V Fung has completed her Doctor of Philosophy in Biochemical Toxicology in Imperial College of Science, Technology & Medicine, London, United Kingdom. She is a UK registered Toxicologist. She has worked as a Regulatory Scientist for over 10 years in the area of pharmaceuticals and industrial chemicals. Presently she is the Principal Inspector in Australia SafeWork NSW’s, hazardous chemicals services group. She has authored over 20 peer-reviewed publications in chemical hygiene and toxicology

Abstract:

Many cytotoxic drugs (CTD) are known human carcinogens. Even low levels of exposure to these chemicals can cause cancer as well as miscarriages, birth defects and other irreversible adverse effects. Stringent control measures are therefore needed to prevent occupational exposure to cytotoxic drugs (CTD) and their wastes. CTD use at 4 compounding pharmacies, 25 human and animal health care centers across New South Wales (NSW) were verified for compliance with Work, Health and Safety (WHS) legislation on the effectiveness of their exposure control measures. A total of four hundred and forty-five (445) surface swab samples were analyzed to detect the restricted carcinogen cyclophosphamide and other CTD. Compliance with the Australian WHS legislation for systematic chemical management, including procedures for safe use of carcinogens, in all workplace visited was satisfactory. Although SDS was available at all workplaces, it is noted, most workers especially veterinary nurses, require further training to raise awareness on the health hazards of CTD. Surface contaminations were detected in surface swab samples collected from locations associated with CTD reformulation, preparation, delivery, storage, treatment and waste disposal. Results suggest that despite having good documentation and safe systems for handling CTD in all workplace visited, CTD contamination was detected even in clean area where no CTD exposure is expected. Level of CTD contaminants ranged from 3.45 to 462 and 4.8 to 7686 mg per sample in health care centers and in compounding pharmacies respectively. The level of contamination was relatively low in health care centers. Highest contamination was detected in an Australian owned compounding pharmacy where high risk task was conducted by a trained professional. To eliminate or minimize workers exposure to CTD contaminant requires a hierarchy of hazard control. Integration of hygiene monitoring into the regulatory documentation verification program can provide an evidence-based approach to change workers’ behavior for a more stringent work practices. Our study shows presence of CTD contamination in most workplaces despite evidence of good systems of chemical management. The contaminations detected appear to be residuals attributed to lack of stringency in workers safe work behavior. Better worker awareness on the health hazards of CTD is recommended to engage workers’ in preventive behaviors.

Biography:

Dyah A Perwitasari has her expertise in pharmacogenetic and pharmaceutical care. She has developed a model of treatment monitoring according to the pharmacogenetic results study, the model which may improve patients’ quality of life by involving the psychological domains of patients. Thus, by combining the personalized medicine monitoring in pharmacogenetic science and assessing patients’ psychological factors, the results of her studies may clinically increase patient’s quality of life.

Abstract:

Statement of the Problem: India, Indonesia and China had the largest number of cases from global total number (23%, 10% and 10%, respectively). There are large variations in the metabolism of the anti-tuberculosis drug-isoniazid, including polymorphisms of the NAT2 gene. This enzyme is markedly decreased in the livers of slow acetylators (SA). The elimination of INH follows a bimodal or trimodal distribution consisting of slow (SA), intermediate (IA) and rapid acetylators (RA). There is a strong correlation between these phenotypes and NAT2 genotypes in Caucasians. Previous studies have reported inconsistent results on whether slow or rapid acetylators are a risk factor for INH-induced hepatotoxicity. The purpose of this study is to determine the association between CYP2E1 polymorphisms and the development of DILI in Indonesians and determine the genotypes and phenotypes related to a change in the risk of DILI. 

Methodology & Theoretical Orientation: A cohort design consisting of 55 Indonesian adult tuberculosis (TB) patients was carried out. Acetylating phenotypes were studied using the metabolic ratio of plasma Ac HZ/HZ. DILI was defined using CTCAV version 4.0. The allelic and genotypic frequency distributions of CYP2E1 rs3813867 were studied using the polymerase chain reaction-amplification refractory mutation system (ARMS) methodology.

Findings: Patients with an INH concentration of more than 7 mg/mL showed a higher risk of developing DILI when compared with patients who showed. a therapeutic range of 3-6 mg/mL INH (OR: 1.3, 95% CI: 0.2-8.2). SAs had a higher incidence of DILI when compared with RAs (OR: 4.6, 95% CI: 1.3-15.9). Meanwhile, subjects with GC had a higher risk of DILI incidence (OR: 4.3, 95% CI: 0.8–24.4).

Conclusion & Significance: Our study shows that polymorphisms of CYP2E1 and SAs may have role in the DILI incidence. Recommendations are needed to be considered by the pharmacists during the adverse drug reaction monitoring.

Biography:

Milu T Cherian has completed her PhD from University of Illinois at Urbana-Champaign in Molecular Physiology from 2007-2011 and had been working as a Teaching Assistant for two years. She is experienced as a Researcher in Chemical Biology and Therapeutics at St. Jude Children’s Research Hospital since September 2012 to present

Abstract:

This study aims to use CINPA1, a recently discovered small molecule inhibitor of the xenobiotic receptor CAR (constitutive androstane receptor) for understanding the binding modes of CAR and to guide CAR-mediated gene expression profiling studies in human primary hepatocytes. CAR and PXR are xenobiotic sensors that respond to drugs and endobiotics by modulating the expression of metabolic genes that enhance detoxification and elimination. Elevated levels of drug metabolizing enzymes and efflux transporters resulting from CAR activation promote the elimination of chemotherapeutic agents leading to reduced therapeutic effectiveness. Multidrug resistance in tumors after chemotherapy could be associated with errant CAR activity, as shown in the case of neuroblastoma. CAR inhibitors used in combination with existing chemotherapeutics could be utilized to attenuate multidrug resistance and resensitize chemo-resistant cancer cells. CAR and PXR have many overlapping modulating ligands as well as many overlapping target genes which confounded attempts to understand and regulate receptor-specific activity. Through a directed screening approach we previously identified a new CAR inhibitor, CINPA1, which is novel in its ability to inhibit CAR function without activating PXR. The cellular mechanisms by which CINPA1 inhibits CAR function were also extensively examined along with its pharmacokinetic properties. CINPA1 binding was shown to change CAR-co-regulator interactions as well as modify CAR recruitment at DNA response elements of regulated genes. CINPA1 was shown to be broken down in the liver to form two, mostly inactive, metabolites. The structure-activity differences of CINPA1 and its metabolites were used to guide computational modeling using the CAR-LBD structure. To rationalize how ligand binding may lead to different CAR pharmacology, an analysis of the docked poses of human CAR bound to CITCO (a CAR activator) vs. CINPA1 or the metabolites was conducted. From our modeling, strong hydrogen bonding of CINPA1 with N165 and H203 in the CAR-LBD was predicted. These residues were validated to be important for CINPA1 binding using single amino-acid CAR mutants in a CAR-mediated functional reporter assay. Also predicted were residues making key hydrophobic interactions with CINPA1 but not the inactive metabolites. Some of these hydrophobic amino-acids were also identified and additionally, the differential co-regulator interactions of these mutants were determined in mammalian two-hybrid systems. CINPA1 represents an excellent starting point for future optimization into highly relevant probe molecules to study the function of the CAR receptor in normal- and patho-physiology and possible development as therapeutics (for e.g., use for resensitizing chemoresistant neuroblastoma cells).

Biography:

Xue Zhang has obtained his Master of Surgery and PhD degrees from University of New South Wales, Australia, and has been working in School of Chinese Medicine, Hong Kong Baptist University since 1999, as a Department Director from 2012 to 2015. He has broad research interest and connections, but in recent year more dedicated to stem cell research and drug delivery for cancer treatment on supervising a PhD student

Abstract:

Hepatocellular carcinoma (HCC) has a fairly high morbidity and is notoriously difficult to treat due to long latent period before detection, multidrug resistance and severe drug-related adverse effects from chemotherapy. Targeted drug delivery systems (DDS) that can selectively deliver therapeutic drugs into tumor sites have demonstrated a great potential in cancer treatment, which could be utilized to resolve the limitations of conventional chemotherapy. Numerous preclinical studies of DDS have been published, but targeted DDS for HCC has yet to be made for practical clinical use. Since rational targeted DDS design should take cancer specific properties into consideration, we have reviewed the biological and physicochemical properties of HCC extensively to provide a comprehensive understanding on HCC and recent DDS studies on HCC, aiming to find some potential targeted DDSs for HCC treatment and a meaningful platform for further development of HCC treatments. 

Biography:

Kevser Erol has completed his PhD at the age of 29 years from Dicle University and postdoctoral studies from Anadolu University School of Medicine.She is the director of deprtment of Pharmacology. She has published more than 125 papers in reputed journals

Abstract:

Objective: Cisplatin is a commonly used antineoplastic agent for the treatment of several solid tumors. Peripheral neuropathy is one of its major side effects. Agmatine has been shown to relieve neuropathic pain in different animal models. Cannabinoids have also shown analgesic features in neuropathic pain models. The aim of this study was to investigate the effects of anandamide, a cannabinoid receptor agonist and agmatine on cisplatin-induced neuropathy.

Materials & Methods: Neuropathy was induced in male Wistar rats (250-300 gm, n=6) by intra-peritoneal injections of cisplatin (3 mg/kg once a week for five consecutive weeks). The development of neuropathy was evaluated using tests for both mechanical allodynia and heat-hypo/hyperalgesia. After 5 weeks of treatments, cardiac perfusion with para-formaldehyde was performed and dorsal root ganglion (DRG) neurons were collected for further electron microscopic evaluation. Single dose of agmatine (100 mg/kg) or anandamide (1 mg/kg) was given intra-peritoneally. The development of neuropathy was evaluated using tests for both mechanical allodynia and heat-hypo/hyperalgesia. Spontaneous locomotor activity, rectal temperature, anti-nociception and catalepsy were evaluated for cannabinoid tetrad. After 5 weeks of treatments, cardiac perfusion with para-formaldehyde was performed and dorsal root ganglion (DRG) neurons were collected for further electron microscopic evaluation.

Results: Cisplatin treatment induced mechanical allodynia and thermal hyperalgesia. Single dose of agmatine significantly attenuated cisplatin-induced mechanical allodynia.

Biography:

Abayomi Oguntunde has his expertise in African Traditional Medicine (ATM) particularly diabetes. His research interest is in the use of herbal recipe in the treatment of chronic metabolic diseases

Abstract:

Biotechnology is a critical propelling force backing the current global science and technology development and bio-industry has become a center of attention of international competition. Many countries have developed national strategies, formulated policies and substantially increased investment in biotechnology, subsequently making it a deliberate priority in global competitiveness. Biotechnology has assumed significant strategic importance in addressing major issues facing the world such as population growth, health, food security sustainable energy and environmental protection. Biotechnology research outcomes includes a diversity and varieties of technological developments that has meaning impact on all aspect of agriculture for sustainable food production, processing and consumption; environmental protection to combat climate change, renewable energy for clean and sustainable power and health management for drug discovery, development and delivery to accurate disease diagnosis and treatment. Ethno-medicinal plants in both developed and developing countries are alive with rare species that possess pharmacologically active constituents, ingredients or compounds for possible cure of many chronic diseases such as cancers, HIV/AIDS, neurological disorders, metabolic diseases and probably sickle cell anemia. From the available literature, most of these plants bio accumulate such compounds in minute quantities that are not enough to characterize and biotechnology has become the appropriate modern tool to unravel the quantity, quality and specific characteristics of these active ingredients. It has illuminated more deeply and more extensively many genetic, chemical, physiological and mathematical processes which can be used to mass produce biologically active compounds in plants. The main objective of the study is to bring to fore the advance in marriage of biotechnology techniques and ethnomedicinal plants. This will further strengthened research collaborations and partnerships involving botanist, biotechnologist, chemists, geneticists, etc., further strengthening better health care delivery and management.

Biography:

Leandro Bueno Bergantin has received his academic education at UNIFESP-EPM, Brazil and UAM, Spain, completed his degree in Biomedicine in 2008, MSc in 2010 and PhD in 2014. His research involves cell signaling mediated by Ca²⁺ and cAMP, skeletal and smooth muscles, peripheral and central nervous systems. His research work solved the enigma of the paradoxical effects produced by L-type Ca²⁺ channel blockers.

Abstract:

The calcium paradox phenomenon has been discovered in 1970’s due to experiments performed in vas deferens. Briefly, experimental studies using vas deferens showed that neurogenic responses were completely inhibited by L-type Ca²⁺ Channel Blockers (CCBs) in high concentrations but paradoxically potentiated in low concentrations, so characterized as a calcium paradox phenomenon. In addition, several clinical studies have been reporting that administration of L-type CCBs, drugs largely used for antihypertensive therapy such as Verapamil and Nifedipine, produces reduction in peripheral vascular resistance and arterial pressure, associated with a paradoxical sympathetic hyperactivity. Despite this sympathetic hyperactivity has been initially attributed to adjust reflex of arterial pressure, the cellular and molecular mechanisms involved in this paradoxical effect of the L-type CCBs remained unclear for four decades. We discovered in 2013 that the calcium paradox phenomenon produced by L-type CCBs in vas deferens is due to Ca²⁺/cAMP interaction, which could properly explain the paradoxical sympathetic hyperactivity produced by L-type CCBs in clinical studies. Then, the pharmacological manipulation of the Ca²⁺/cAMP interaction could represent a potential cardiovascular risk for hypertensive patients due to increase of sympathetic hyperactivity. In contrast, this pharmacological manipulation could be a new therapeutic strategy for increasing neurotransmission in psychiatric disorders such as depression and producing neuroprotection in the neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. In fact, CCBs truly show cognitive-enhancing abilities and reduce the risk of dementia, including Alzheimer's, Parkinson’s disease and others. The molecular mechanisms involved in these pleiotropic effects remain under debate whether Ca²⁺/cAMP interaction is involved in CCBs pleiotropic effects deserves special attention. Cellular homeostasis of Ca²⁺ and/or cAMP in these cells could be a novel therapeutic target for medicines. By reducing Ca²⁺ influx, CCBs may increase [cAMP]c by enhancing adenylyl cyclase activity, which increases neuroprotection. cAMP also enhances the release of Ca²⁺ from endoplasmic reticulum, which increases exocytosis. Considering our model in which increment of [cAMP]c stimulates Ca²⁺ release from endoplasmic reticulum, it may be plausible the therapeutic use of the PDE inhibitor rolipram in combination with low doses of CCBs to stimulate neuroprotection and enhance neurotransmission by increasing neurotransmitter release in the areas of central nervous system involved in neurological/psychiatric disorders in which neurotransmission is reduced, including Alzheimer’s and Parkinson’s diseases.