Location: University of Manitoba Brodie Centre, Apotex Centre and Ambassador Room in Canad Inns Winnipeg, MB. 1 P a g e

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1 Canadian Society of Pharmacology and Therapeutics 204 Scientific Meeting Program In conjunction with the Canadian Student Health Research Forum (CSRHF) Location: University of Manitoba Brodie Centre, Apotex Centre and Ambassador Room in Canad Inns Winnipeg, MB P a g e

2 Welcome from CSPT President Dear Colleague: Welcome to Winnipeg, the host city of the 6th Annual Meeting of Canadian Society for Pharmacology and Therapeutics (CSPT)! Let me first acknowledge that our two local organizers, Dr. Fiona Parkinson and Dr. Donald Miller, who are from University of Manitoba, along with our executive administrator, Kathy Gaebel, have been instrumental in crafting this year s fantastic meeting. This meeting offers not only chances to share novel scientific findings, but also numerous opportunities for networking across various areas in pharmacology and toxicology. For trainee participants, I encourage you to talk to fellow students and faculty members, so that you can appreciate the breadth and depth of the discipline of Pharmacology & Toxicology. As scientific program co-chairs, Dr. Donald Miller and Dr. Michael Rieder (Western) have assembled an exciting program, featuring a Trainee workshop, and three symposia addressing Medical Toxicology, Neurological Disturbances in Diabetes, and Cardiovascular Drug Toxicity. This year, we will join the Canadian Student Health Research Forum (CSRHF), and the first day (June 0) will be a trainee-focused joint session, which will provide an excellent information sharing opportunity for student participants. We always look forward to trainee poster and oral presentations, which will take place on Wednesday June and Friday June 3 this year. At the end of the meeting, we will have a session called Practical Pharmacology and Toxicology, organized by a clinical pharmacologist Dr. George Dresser (Western), which will address clinical issues of pharmacological and toxicological importance. This informal discussion session offers a chance to witness how advances in basic scientific knowledge and discovery in pharmacology are being translated into improved patient care. I am certain that the discussion will also help us identify key research questions in both basic and clinical pharmacology areas. CSPT embraces broad fields of basic and clinical pharmacology/toxicology. The resultant breadth and depth is the strength of our discipline. To maximize our forte, we need to engage in truly crossdisciplinary activity. I believe that our annual meeting is essential for us to achieve this goal. Sincerely, Shinya Ito, MD, FRCPC President 2 P a g e

3 Tuesday June 0 2:00 6:30 Registration (Brodie Centre Atrium) 2:00 3:00 CSHRF Drewry Lecture- Speaker: Jillian Stobbart 3:00 6:30 CIHR Career Development Workshop 3:00 6:30 CSPT Trainee Workshop: IMAGING MODALITIES FOR TRANSLATIONAL RESEARCH (Rm 07 Apotex Centre, 750 McDermot Ave) Leading researchers will introduce attendees to many in vivo and bioimaging methodologies. These methodologies have applications for pre-clinical, translational and/or clinical research. Using bioimaging to visualize pathological processes, biomarker levels, and drug responses can provide more than just beautiful photographs! 3:00 4:00 Michael Jackson, (University of Manitoba, Winnipeg, MB) An Introduction to Small Animal Imaging 4:00 4:45 Demonstration (limited to a maximum of 60 participants) 4:45 5:30 Demonstration 2 (limited to a maximum of 60 participants) 5:30 6:30 General discussion & refreshments 9:00-20:30 CSPT Executive Board Meeting (Invitation only) (Heartland, Delta Winnipeg) Wednesday June 08:00 08:30 Breakfast (Brodie Centre Atrium & Canad Inns (students)) 08:30 :00 CSPT Poster Judging (Brodie Centre Atrium) :00 2:00 CSPT SENIOR SCIENTIST AWARD RECIPIENT LECTURE (Rm 07 Apotex Centre, 750 McDermot Ave) Peter Smith (University of Alberta, Edmonton AB) Frogs, Pain and Serendipity 40 years of Drugs on the Brain 2:00 3:30 Lunch (Brodie Centre Atrium) 3:30 4:30 STRATEGIES FOR OBTAINING - AND KEEPING - A POSITION AS A CLINICIAN SCIENTIST (Frederic Gaspard Lecture Theatre (A), Basic Medical Sciences Bldg) Moderator: Dr. Kent HayGlass; Panelists Dr. Cheryl Rockman-Greenberg and Dr. Richard Keizer 4:30 7:00 CSPT Symposium IMPORTANT CONCEPTS IN MEDICAL TOXICOLOGY (Rm 07 Apotex Centre, 750 McDermot Ave) Chair: David Juurlink (Institute for Clinical Evaluative Sciences, Toronto) Marco Sivilotti: (Queen s University, Kingston ON) Massive Acetaminophen Overdose: Old Drug, New Toxidrome Margaret Thompson (Ontario Poison Center, Toronto, ON) Fact or Fiction: evidence for selected popular toxicology myths/truths 3 P a g e

4 David Juurlink: (Sunnybrook Hospital, Toronto, ON) Advances in Antidote Therapy 7:30 Trainee Supper (provided by CSHRF, Lower Fort Garry) Dep t of Pharmacology Chairs dinner (invitation only) the Forks Market Thursday June 2 08:00 09:00 Breakfast (provided by CSHRF, Basic Medical Sciences Bldg Concourse) 09:00 6:30 CSHRF Diabetes Symposium: NATURE AND NURTURE (Frederic Gaspard Lecture Theatre (A), Basic Medical Sciences Bldg) Morris White (Harvard University, Cambridge, MA) Integrating molecular strategies to prevent and cure diabetes Francine Kaufman (Children s Hospital, Los Angeles, CA) Path to the Artificial Pancreas Rob Nelson (NIH, Phoenix, AZ) Diabetes and Its Complications in Aboriginal People: Lessons from the Pima Indians Frank Gonzales- (NCI NIH, Bethesda, MD) A new drug target for obesity, insulin resistance and fatty liver disease Andre Carpentier (Sherbrooke University, Sherbrooke, QC) Islands in oil slicks: surfing on the lipotoxic wave 6:30 7:30 CSPT DISTINGUISHED SERVICE & EDUCATION AWARD RECIPIENT LECTURE (Rm 07 Apotex Centre, 750 McDermot Ave) Shinya Ito (Hospital for Sick Children, Toronto ON) An insider's view of a Discipline of Pharmacology 8:00 20:00 CSPT annual dinner (Bergmann s on Lombard) (ticket required) Friday June 3 08:00 08:30 CSPT Breakfast (Ambassador A, Canad Inns) 08:30 09:30 CSPT Trainee Oral Presentations (Ambassador A, Canad Inns) 09:30 2:00 CSPT Symposium 2: SPECTRUM OF NEUROLOGICAL DISTURBANCES IN DIABETES (Ambassador A, Canad Inns) Chair: Michael Jackson (University of Manitoba, Winnipeg MB) Douglas Zochodne (University of Calgary, Calgary AB) Neurological complications of Diabetes 4 P a g e

5 :00-:5 Break Paul Fernyhough (University of Manitoba, Winnipeg MB) Muscarinic receptor antagonism as a novel mechanism for sensory nerve repair. Jack Jhamandas (University of Alberta, Edmonton AB) Beta Amyloid-Induced Depression of Hippocampal Long-Term Potentiation Is Mediated through the Amylin Receptor. Hong-Shuo Sun (University of Toronto, Toronto ON) Neuroprotective role of ATP-sensitive potassium channels in cerebral ischemia. 09:30 2:00 CSPT Symposium 3: TRANSLATIONAL PERSPECTIVES ON CARDIOVASCULAR TOXICITY (Ambassador B, Canad Inns) Chair: George Dresser (University Hospital, Western University, London, ON) :00 -:5 Break George Dresser (University Hospital, Western, London ON) Perspectives Muhammad Mamdani (Applied Health Research Centre, Toronto ON) Signal detection for adverse cardiac events from large databases Rommel Tirona (Western University, London ON) Mechanisms of statin toxicity Pawan Singal (St Boniface Hospital Research Centre, Winnipeg, MB) Pathogenesis and prevention of oxidative stress-mediated Doxorubicin induced heart failure. 2:00 3:30 Lunch - Annual General Assembly & Awards Ceremony (Ambassador A, Canad Inns) 3:30 5:30 PRACTICAL PHARMACOLOGY AND TOXICOLOGY (Ambassador A, Canad Inns) Folefac Aminkeng (University of British Columbia, Vancouver, BC) Pharmacogenetic Testing to Prevent Anthracycline-induced Cardiotoxicity Ahmed Ziada (London Health Sciences Center, London, ON) Anticoagulation management in a patient with Cushings syndrome on ketoconazole Gal Neuman (Hospital for Sick Children, Toronto, ON) () TDM for managing lactation related toxicity of antidepressants (2) Preconceptional Monitoring of Mercury Levels in Hair and Blood as a Tool for Minimizing Associated Reproductive Risks Leah Mwai (University of British Columbia, Vancouver, BC) Genomics for decision support in cisplatin associated hearing loss 5 P a g e

6 Steven Gryn (Western University, London, ON) Impact of a genomics guided algorithm for management of warfarin dosing in medical inpatients Panel discussion 5:30 Meeting close Speaker Abstracts and Biosketch Wednesday June CSPT Senior Scientist Award Recipient Lecture Dr. Peter Smith - Department of Pharmacology, University of Alberta Frogs, Pain and Serendipity 40 years of Drugs on the Brain When I entered science in the early 970 s the idea of neuromodulation was really in its infancy. Synaptic events were assumed to occur within the 0 s of milliseconds so the discovery of slow synaptic potentials in autonomic ganglia, particularly amphibian sympathetic ganglia, was a major focus of research at the time. As a postdoctoral fellow at NIMH, I was given the task of identifying the intracellular second messenger system involved in the generation of these slow synaptic events. This question was repeatedly visited by my research group over the next 30 years! It was really a serendipitous observation that led us to identify phosphatidylinositol 4,5 bisphosphate as the second messenger in question, although it did not appear to work in the conventional way in this system. By the 980 s amphibian sympathetic ganglia had become a very well defined neuronal system and we were encouraged to use them to study aspects of nerve injury and how this may relate to neuronal regeneration. It was straight forward academic curiosity that led us to study other ganglionic neurons; those of rodent dorsal root ganglia. Serendipity intervened again. We realized that by studying the electrophysiological consequences of nerve injury in these neurons that we actually providing urgently needed insight into the cellular mechanisms of neuropathic pain. This type of chronic pain can occur as a result of traumatic nerve injury and is frequently encountered in cases of diabetic, postherpetic or HIV-AIDs associated neuropathy or with fibromyalgia or multiple sclerosis. Analysis of neuropathic pain mechanisms and the actions of drugs such as gabapentinoids at the spinal and peripheral level thus remains the major research thrust of my laboratory today. Our most recent findings prompted us to test the effectiveness of the anti-angina agent, ivabradine in animal models of neuropathic pain. It worked really well! Peter Smith obtained his PhD from Southampton University. After postdoctoral studies at NIMH, St Elizabeth s Hospital, Washington DC and at McGill University, he joined the Department of Pharmacology at the University of Alberta as one of the first cohort of AHFMR scholars in 980. He has over 00 peerreviewed publications in the fields of neuropharmacology, autonomic pharmacology, neurosciences and pain mechanisms. Toxicology Symposium Marco Sivilotti - Professor, Dept s Emergency Medicine, and Biomedical and Molecular Sciences, Queen s University) Massive Acetaminophen Overdose: Old Drug, New Toxidrome While every medical toxicologist is familiar with acetaminophen overdose, even an old dog has new tricks. Very large ingestions (~g/kg) can cause coma, lactic acidosis, hyperglycemia and hypothermia within hours, reflecting impaired ATP synthesis. This toxidrome of mitochondrial paralysis is largely reversible 6 P a g e

7 with treatment, which may include higher doses of acetylcysteine and hemodialysis. But understanding the underlying mechanism is expanding our understanding of our favourite drug. Dr. Sivilotti is Associate Professor of Emergency Medicine, and of Biomedical and Molecular Sciences at Queen s University in Kingston, Ontario, Canada. He completed residency training in emergency medicine at McGill University in Canada, and fellowship training in medical toxicology at the University of Massachusetts in the United States, and is board certified in both specialties. He has previously been on faculty at the University of Ottawa and Harvard Medical School, and is currently on staff at the Kingston General and Hotel Dieu Hospitals. He also serves as medical consultant to the Ontario Poison Centre in Toronto. Margaret Thompson - Medical Director, Ontario Poison Centre Fact or Fiction: evidence for selected popular toxicology myths/truths Using cases from the files at the Poison Centre, evidence for selected popular toxicology myths/truths will be presented. Was Rudy Eugene really high on bath salts when he ate Ronald Poppo s face? Will oximes help in a sarin attack? Has the Stone Heart ever been described? Will glucagon improve cardiac inotropy and/or chronotropy in overdoses? Margaret Thompson, MD, FRCPC, FACMT is currently the Medical Director of the Ontario and Manitoba Poison Centres, the Program Director for Clinical Pharmacology and Toxicology at the University of Toronto, and an Emergency Physician at St. Michael s in Toronto. She is trained in Emergency Medicine and Medical Toxicology and is an Assistant Professor at U Toronto. David Juurlink - Sunnybrook Health Sciences Centre Advances in Antidote Therapy While good supportive care is the cornerstone of treatment of most poisoned patients, antidotes are sometimes employed for specific toxins. This presentation will use clinical cases to discuss the mechanism, effectiveness and safety of selected antidotes. David Juurlink received degrees in Pharmacy and Medicine from Dalhousie, followed by specialization in Internal Medicine, Clinical Pharmacology, Medical Toxicology and a PhD in Clinical Epidemiology at the University of Toronto. He is now staff physician in the Division of Internal Medicine at Sunnybrook Hospital, Head of the Division of Clinical Pharmacology at the University of Toronto and a Medical Toxicologist at the Ontario Poison Centre. Thursday June 2 CSPT Distinguished Service & Education Award Recipient lecture Dr. Shinya Ito - Director, Div Clinical Pharmacology, Hospital for Sick Children An insider's view of the Discipline of Pharmacology Shinya Ito, MD, FRCPC, Professor and Head, Division of Clinical Pharmacology & Toxicology; Senior Scientist, Research Institute; Clinician Scientist Cross-appointed in Departments of Pharmacology & Toxicology, Medicine, and Pharmaceutical Sciences. Chair of SickKids Drugs & Therapeutics committee. Established the Antimicrobial Stewardship Program and is leading pharmacogenetics program at Sickkids. He graduated from Jichi Medical School, Japan, in 979. Served as a general practitioner/paediatrician in remote areas of Japan before coming to Toronto as a clinical fellow in Division of Clinical Pharmacology & Toxicology (supervisor: Dr. Gideon Koren). Joined the staff of the Department of Paediatrics, Division of Clinical Pharmacology & Toxicology and presently is the Division Chief. 7 P a g e

8 Friday June 3 Spectrum of Neurological Disturbances in Diabetes Symposium Douglas Zochodne Department of Clinical Neurosciences, University of Calgary Neurological Complications of Diabetes Diabetes mellitus (DM) targets the nervous system. Polyneuropathy (DPN) can be identified in over 50% of diabetic subjects, resulting in one of the most common neurological disorders. DM renders a double hit on the peripheral nervous system (PNS): (i) DPN, a degenerative, sensory prominent peripheral nerve disorder that targets distal nerve terminals initially, and (ii) attenuated regeneration that limits recovery from neurological damage. In addition to DPN, DM is associated with focal, or localized nerve damage such as carpal tunnel syndrome and other neuropathies and with changes in the central nervous system (risk of infarction, leukoencephalopathy [white matter disease] and cognitive decline). In the PNS, multiple mechanisms, usually centering around glycemia-related damage to sensory neurons are considered including oxidative and nitrative stress, polyol accumulation, glycosylation of neuron proteins, microangiopathy and loss of trophic support. Our laboratory has been interested in the concept that abnormalities of insulin neurotrophic support play a role in its pathogenesis. Insulin is a potent growth factor for sensory neurons and its lack, or resistance to its actions in neurons may contribute to degenerative DPN. Related molecular players in DPN include GLP-, HSP27 and more recently PTEN, a tumour suppressor molecule that is upregulated in diabetic neurons and acts as a brake on neuron plasticity. A important theme of our work has been that DPN involves specific targeting of molecular machinery at the level of the neuron cell body, or perikarya. New avenues to treat this intractable disorder are urgently required. [Supported by CIHR, CDA, AIHS and NIH] Douglas Zochodne is a Professor, Department of Clinical Neurosciences, University of Calgary and the Hotchkiss Brain Institute. He trained in medicine and subsequently Neurology at the University of Western Ontario. He completed fellowships in Neuromuscular disease with Dr. Charles Bolton at Western and Drs. Phillip Low and Peter Dyck at Mayo Clinic. He is a consultant Neurologist of Alberta Health Services, Calgary zone and serves as the Director of the Neuromuscular Clinic (Adult), University of Calgary and as Director of Clinical Neurophysiology (Adult EMG). Paul Fernyhough - St Boniface Hospital research Centre and Department of Pharmacology & Therapeutics, University of Manitoba Muscarinic receptor antagonism as a novel mechanism for sensory nerve repair Adult sensory neurons exhibit a cholinergic phenotype and activity of the muscarinic acetylcholine type receptor (MR) inhibits axonal plasticity. Application of MR selective antagonists, or genetic ablation of MR, resulted in enhanced levels of axonal outgrowth (in vitro) and repair of distal intraepidermal nerve fiber (IENF) loss in the hind paw of rodent models of type and type 2 diabetes. Antimuscarinic drugs, such as pirenzepine and VU (a highly selective MR antagonist available commercially), were able to reverse sensory loss in streptozotocin (STZ)-diabetic rodents. An important translational element is the capacity of topically applied pirenzepine to prevent hypoalgesia and IENF loss in streptozotocin (STZ)- diabetic and type 2 diabetic mice (with no impact on the contralateral hind paw IENF levels). Mechanistic studies show that blockade of MR results in altered Ca 2+ signaling and enhanced mitochondrial function. Investigation of mitochondrial bioenergetics in cultured neurons from diabetic rodents reveals that MR selective antagonism enhanced spare respiratory capacity a key measure of mitochondrial capability to deliver ATP under conditions of high demand and/or stress. We have identified selective antagonists of the MR as novel inducers of AMP-activated protein kinase (AMPK), a regulator of mitochondrial biogenesis, regeneration and physiology. Dr. Fernyhough received a B.Sc. degree in Biological Sciences at the University of Essex, and a PhD in biochemistry in the Department of Biochemistry, University of Sheffield in the UK. He performed postdoctoral research at Colorado State University, Kings College London and as a Wellcome Trust Postdoctoral Fellow at St Bartholomew s Medical College. He subsequently worked as a fully tenured lecturer in the School of Biological Sciences (now the Faculty of Life Sciences) at the University of Manchester. Dr. Fernyhough came to Winnipeg in 2004 and has helped to set up a neuroscience research group at St Boniface Hospital Research Centre with strong links with the Department of Pharmacology & Therapeutics at the University 8 P a g e

9 of Manitoba. Dr. Fernyhough s general research interest is in the cell biology underlying neurodegenerative disorders of the peripheral and central nervous systems with a focus on the impact of diabetes. Jack Jhamandas -Professor, Division of Neurology, Department of Medicine, University of Alberta Role of the pancreatic peptide amylin and its receptor in Alzheimer s disease Amylin (islet amyloid polypeptide) and amyloid beta protein (Aβ), identified as proteinaceous deposits within the pancreas of diabetics and the brain of Alzheimer s patients respectively, share many biophysical, physiological and neurotoxic properties. Although no specific Aβ receptor has been identified, emerging evidence suggests that the amylin receptor serves a putative target receptor for the actions of Aβ in the brain. The amylin receptor consists of the calcitonin receptor that is dimerized with receptor activitymodifying proteins and is widely distributed within central nervous system. Our previous work has shown that the cellular and neurotoxic effects of Aβ are expressed through the G protein-coupled amylin receptor. This presentation will review the functional consequences of amylin receptor blockade that are observed in in vitro and in vivo paradigms of memory and spatial learning. Accumulating evidence suggests that amylin and amylin receptors are involved in aspects of neurodegenerative pathophysiology. Developing therapeutic strategies aimed at modulating amylin receptor function may prove useful for treatment of neurodegenerative diseases such as Alzheimer s disease. Jack Jhamandas is currently Distinguished University Professor in the Division of Neurology, Department of Medicine at the University of Alberta. He received his BSc in Applied Physics and MSc in Biophysics from the University of Alberta, his MD from the University of Calgary, and completed his clinical training in Internal Medicine at the Toronto Western Hospital and in Neurology the Montreal Neurological Institute. He received his PhD in Neuroscience from McGill University. He is a practicing Neurologist and Neuroscientist whose research interests focus on mechanisms underlying cell death in Alzheimer's disease and aspects of Brain control of cardiovascular function. His research program has been funded by the Canadian Institutes of Health Research (CIHR), Heart and Stroke Foundation of Canada, Natural Sciences and Engineering Research Council, Alberta Heritage Foundation for Medical Research, Alberta Ingenuity Fund and the Alberta Prion Research Institute, the Alzheimer's Societies of Canada and Alberta and NWT, and the University Hospital Foundation. In recognition of his scholastic endeavors, Dr. Jhamandas has received the Gold Medal in Medicine from the Royal College of Physicians and Surgeons of Canada; a Killam Professorship; the Department of Medicine Research Achievement Award; held a Tier Canada Research Chair in Alzheimer's Research; and has been elected as a Fellow of the Canadian Academy of Health Sciences and the American Neurological Association. Hong-Shuo Sun - Assistant Professor, Departments of Surgery, Physiology and Pharmacology, Institute of Medical Science, Faculty of Medicine, University of Toronto Neuroprotective role of ATP-sensitive potassium channels in cerebral ischemia Stroke and diabetes are major public health concerns, and the related illnesses cost the Canadian healthcare system $2.5 billion for stroke and $2.2 billion for diabetes in 200 (Canadian Stroke Congress and Canadian Diabetes Association). Stroke is the second leading cause of mortality and immobility in Canada and in the world. The disabilities afflicted in stroke survivors have also created significant social and economic impacts on our society. People with diabetes are at very high risk of cardiovascular disease and stroke. As diabetes becomes epidemic in our society (with ~3-5% prevalence in the world population and the fourth leading cause of death in chronic diseases), the incidence of stroke will escalate in diabetic patients. Yet, the mechanisms underlying high incidences of stroke and heart attack in the diabetic population remain unclear. We know that stroke in diabetics is a clinical culmination of various insults to cerebral vasculatures associated with hyperglycemia. Thus, understanding the cellular and molecular mechanisms underlying stroke-related brain injury in patients with diabetes and the development of potential therapeutics for stroke in diabetics are important goals of medical research as well as public health. KATP channels play an important role in insulin secretion as well as cytoprotection during ischemia. KATP channels link to metabolic disorders and many forms of diabetes, and diabetes is known to cause higher incidences of stroke and heart attack by up to 5 times. Thus, KATP channel is a therapeutic target for drug development for stroke, especially stroke in diabetes. Dr. Hong-Shuo Sun is currently an Assistant Professor in Division of Anatomy, Department of Surgery, Faculty of Medicine, University of Toronto. He also holds cross-appointments in the Departments of 9 P a g e

10 Physiology, and Pharmacology and Toxicology. Hong graduated in Zhongshan Medical College, Sun Yat- Sen University, and completed his training as a cardiologist in the Department of Cardiology of Internal Medicine at the First University Hospital of Zhongshan Medical College, Guangzhou, China. He came to Canada for his graduate study, completed a MSc degree in Pharmacology and Pharmaceutical Sciences in the Faculty of Pharmacy, University of Alberta, and later a PhD in Neurosciences, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary. His postdoctoral training was completed at the University of Toronto. His research interests are in studying the role of ion channels in neuroprotection against cerebral ischemia and stroke, and identifying potential therapeutic targets for stroke. The experimental approaches used in his lab include in-vivo animal models of human diseases in combination with genomic and proteomic analyses, molecular biology, biochemistry, pharmacology, cell culture, advanced imaging (Laser Doppler Flowmetry, Laser Doppler Imager, and Laser Confocal microscopy), electrophysiology, and functional and behavioural assessments. Cardiovascular ToxicitySymposium George Dresser MD FRCPC -Associate Professor at the Schulich School of Medicine and Dentistry, University of Western Ontario Dr. Dresser is an Associate Professor at the Schulich School of Medicine and Dentistry, University of Western Ontario in the divisions of Clinical Pharmacology/Toxicology and General Internal Medicine. He completed his undergraduate and graduate training in Internal Medicine at the University of Western Ontario. After receiving accreditation in Clinical Pharmacology from the Royal College of Physicians and Surgeons of Canada in 999, he completed a post-doctoral fellowship position in Clinical Pharmacology at Vanderbilt University in Nashville, TN and then completed a Ph.D. in Pharmacology & Toxicology. As a clinician, Dr. Dresser has an active practice in vascular disease treatment and prevention, with a special interest in hypertension. He is also is interested in the effects of disease states on drug disposition and effect. He has studied the impact of celiac disease on drug disposition, and has collaborated on research investigating the effects of grapefruit juice, peppermint oil, and St. John s wort on drug effects. He is interested in determinants of patient adherence to drug therapy, and collaborates on drug-drug, diet-drug, and herb-drug interactions research. Muhammad Mamdani, PharmD, MA, MPH - Director Applied Health Research Centre (AHRC), Keenan Research Centre, Li Ka Shing Knowledge Institute of St. Michael s Hospital; Professor, University of Toronto Signal detection for adverse cardiac events from large databases While randomized clinical trials are often regarded as the gold standard approach to studying the efficacy of therapies, they are often limited in their ability to study rare safety issues. Observational epidemiology methods applied to large databases can serve as a powerful approach to detecting safety signals with respect to adverse cardiac events. The objective of this presentation is to contrast the type of information garnered from randomized clinical trials and observational epidemiology for a better understanding of the strengths and limitations of these approaches in examining issues related to therapy safety. The presentation will review principles associated with basic study design, interpretation of findings, and application to clinical practice. Dr. Mamdani is the Director of the Applied Health Research Centre (AHRC), the Keenan Research Centre, Li Ka Shing Knowledge Institute of St. Michael s Hospital in Toronto. He obtained a Doctor of Pharmacy degree (PharmD) from the University of Michigan and completed a fellowship in pharmacoeconomics and outcomes research at the Detroit Medical Center. During his fellowship, Dr. Mamdani obtained a Master of Arts degree in Economics from Wayne State University in Detroit, Michigan. He then completed a Master of Public Health degree from Harvard University with a concentration in quantitative methods, focusing on biostatistics and epidemiological principles. He is also Professor in the Leslie Dan Faculty of Pharmacy and in the Dept of Health Policy, Management and Evaluation of the Faculty of Medicine, and an adjunct Scientist 0 P a g e

11 at the Institute for Clinical Evaluative Sciences (ICES). Dr. Mamdani s research interests include pharmacoepidemiology, pharmacoeconomics, and drug policy. Rommel Tirona Departments of Physiology & Pharmacology and Medicine, Western University Mechanisms of statin toxicity Hydroxy-methyl-glutaryl-Co-A reductase inhibitors (statins) are the most widely prescribed class of medicines in Canada. They are generally well-tolerated, however approximately 5% of statin users will develop myopathy which commonly includes myalgias, but rarely can involve myositis or rhabdomyolysis. In this presentation, we will review current concepts of the mechanisms of statin myopathy including autoimmunity, mitochondrial toxicity and dysregulation of creatine homeostasis. Furthermore, aspects of clinical pharmacology relevant to statin myopathy will be discussed, focusing particularly on clinical and genetic risk factors, impact of drug-drug interactions and class effects. Lastly, strategies for the management of statin intolerance will be discussed with respect to proposed toxic mechanisms. Rommel G. Tirona is Associate Professor in the Departments of Physiology & Pharmacology and Medicine at The University of Western Ontario. He received a B.Sc. in Pharmacy and Ph.D. in Pharmaceutical Sciences at the University of Toronto. After a post-doctoral fellowship in Clinical Pharmacology at Vanderbilt University, he was a Research Scientist in drug discovery and development at Amgen Inc. His research interests include drug transport and metabolism, regulation of gene expression, pharmacogenetics and pharmacokinetics as determinants of drug response and toxicity. Pawan K. Singal - Professor and Director, Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Canada Pathogenesis and prevention of oxidative stress-mediated Doxorubicin-induced heart failure Doxorubicin (Dox) has been frequently used as a frontline chemotherapeutic agent against a variety of cancers. More recently, it has been used as an adjunct therapy. Although tremendous progress has been made on the optimal usage of Dox over the last 40 years, cardiotoxicity still remains a major concern. The great promise is that the mechanisms leading to anti-tumor activity appear to be different from those leading to Dox-induced cardiomyopathy. In this regard, we have provided evidence that cardiomyopathy is mediated by an increase in oxidative stress. Such an increase is a consequence of the drug-increase in the production of oxygen radicals and a simultaneous decrease in antioxidants. The molecular defect appears to be a reduction in glutathione peroxidase activity. Our studies have drawn attention to probucol (Prob), a lipid-lowering agent with potent antioxidant properties, which provides complete protection against Dox-induced cardiomyopathy. We also documented that an adjunct therapy with Dox and Prob does not interfere with the antitumor properties of Dox in an experimental setting. (Supported by the Heart and Stroke Foundation of Manitoba and CIHR.) Dr. Pawan Singal is a professor of Physiology and is Director of the Institute of Cardiovascular Sciences, St. Boniface Hospital and the University of Manitoba, Winnipeg, Canada. Dr. Singal completed his B.Sc. Hons and M.Sc. in Biophysics from Punjab University, India; Ph.D. in Physiology from the University of Alberta. After 3 years in Saskatoon, Canada, as a Post-Doctoral Fellow of the Medical Research Council, Dr. Singal joined the Physiology Department at the University of Manitoba. He then received a D.Sc. degree in Cardiovascular Pathophysiology. He served as Associate Dean for the Faculty of Graduate Studies, University of Manitoba. Internationally he is known for his work on oxidative stress and heart failure and has made significant contributions in our understanding of the role of cytokines in the sequeale of heart failure due to doxorubicin, chronic pressure overload as well as myocardial infarction. P a g e

12 Submitted Abstracts - Effects of cyclic cadherin peptide, Ala-Asp-Thr (cadt) on blood brain barrier (BBB) integrity: Potential applications for enhancing drug delivery to the brain. On, Ngoc ; Laksitorini, Marlyn 2 ; Kiptoo, Paul 2 ; Siahaan, Teruna 2 ; Miller, Donald University of Manitoba, Winnipeg, MB, Canada; 2 University of Kansas, Lawrence, Kansas, USA Objectives: To examine the effects of a cyclic cadherin peptide, containing the Ala-Asp-Thr (cadt) sequence, on BBB integrity. Methods: The effect of cadt peptide on BBB permeability was examined in Balb/c mice specifically focusing on both the time frame for modulation of BBB permeability and the magnitude of BBB disruption. Blood-brain barrier permeability was assessed with gadolinium contrast agent (Gd-DTPA; a small hydrophilic permeability marker), under control conditions and following exposure to cadt (0. - using magnetic resonance imaging (MRI). Administration of imaging agents and cadherin peptide was done through bolus tail vein injections. Results: Under control conditions, very little Gd-DTPA entered the brain. Mice treated with cadt displayed a dose-dependent increase in BBB permeability as assessed with Gd-DTPA enhanced MRI with doses of - (4-fold) in Gd-DTPA entry into the brain. The increase in BBB permeability was rapid, occurring within 6-9 minutes following the administration of the cadherin peptide. While there were regional differences in baseline BBB permeability, the cadt peptide produced similar increases in BBB permeability throughout all regions examined. The cadt peptide produced increases in BBB permeability that lasted for more than 2 hrs following the injection of the peptide. Complete restoration of BBB integrity was observed within 4-6 hrs of cadherin peptide administration. Conclusions: The cyclized cadherin peptide produced a rapid and reversible increase in BBB permeability. The use of the cadherin peptides in combination with therapeutic agents can enhance drug delivery to the brain. 2 - The role of adiponectin deficiency in the development of gestational diabetes mellitus Moyce, Brittany; Dolinsky, Vernon; Pereira, Troy; Fonseca, Mario University of Manitoba, Winnipeg, MB Objectives: To observe the relationship between adiponectin deficiency and the development of gestational diabetes using adiponectin knock-out mice and high-fat and sucrose diet induced gestation diabetes mellitus (GDM). Previously we have shown that adiponectin is reduced in rats with GDM, and we propose that adiponectin null mice will be at higher risk for development of GDM. Methods: To induce GDM in pregnant mice, female mice are fed a high fat and sucrose (HFS) diet and are compared to low fat-fed lean controls. Adiponectin knockout mice (strain B6;29-AdipoqtmChan/J) are used as a model of adiponectin deficiency and compared to C57/BL6 wild type control mice. The female mice are bred with males of the same genotype. Weight and food consumption are monitored weekly, and blood was collected at each trimester of pregnancy to measure insulin and adiponectin levels. To assess insulin sensitivity, a glucose tolerance test was performed in the third trimester. Results: Pregnant adiponectin knockout mice exhibited higher fasting blood glucose and insulin levels compared to their respective wild-type controls. In addition, adiponectin knockout mice had impaired glucose tolerance. Body weights and food consumption during pregnancy were not significantly different between the genotypes. Conclusions: Pregnant adiponectin knockout mice have high fasting blood glucose, hyperinsulinemia and severely impaired glucose tolerance relative to wild type controls, which is characteristic of GDM. Our results suggest that adiponectin deficiency contributes to the development of GDM. 3 - The influence of shape on cellular uptake and magnetic targeting of iron oxide nanoparticles Sun, Zhizhi ; Worden, Matthew 2 ; Hegmann, Torsten 2 ; Miller, Donald ; Thliveris, James University of Manitoba, Winnipeg, MB; 2 Kent State University, Kent, OH USA 2 P a g e

13 Objectives: Our laboratory is examining iron oxide nanoparticles (IONPs) as a potential platform for increasing drug delivery to the brain. While much effort has focused on grafting ligand onto the IONP surface to enhance cellular uptake in brain endothelial cells, herein we report alteration of IONP shape can influence both the preferential cellular uptake in endothelial cells and the ability to augment cell uptake with application of an external magnetic field. Methods: Nanosphere and nanoplatelet shaped IONPs with the same size and negative surface charge were synthesized. Cellular uptake profiles of nanosphere and nanoplatelet IONPs were compared in brain and lung endothelial cells, as well as liver, intestine, and kidney epithelial cells. Quantitative determination of cellular IONP was performed using ferrozine assay. Transmission electron microscopy (TEM) was used to confirm the internalization of IONPs. Toxicity of both IONP compositions was determined using MTT assay. Results: Uptake of nanospheres was minimal in all cells tested with or without magnetic field exposure. In contrast, a 3-fold enhancement in internalized nanoplatelets was observed in endothelial cells compared to nanosphere compositions. Exposure of external magnetic field increased nanoplatelet uptake in endothelial cells by 0 fold. The uptake of nanoplatelets in epithelial cells was 3 times lower than endothelial cells. TEM confirmed preferential uptake of nanoplatelets in endothelial cells. No toxicity was observed in endothelial cells treated with nanoplatelets. Conclusions: Nanoplatelets have improved cellular uptake profiles compared to nanospheres. The increased cellular uptake of the nanoplatelets was especially apparent in endothelial cells. The increased magnetic properties of the nanoplatelets result in enhanced uptake in the presence of an external magnetic field. These properties may allow for better cellular penetration across capillary beds such as the bloodbrain barrier. Support provided by NSERC-CIHR Collaborative Health Research Project. 4 - Synthetic CXCR4 Chemokine Receptor Agonists Alter the Pathway Dogma of Chemotaxis. Escher, Emanuel ; Lefrancois, Marilou ; Mona, Christine ; Cabana, Jérôme ; Lavigne, Pierre ; Leduc, Richard ; Marsault, Éric ; Heveker, Nikolaus 2 Université de Sherbrooke, Sherbrooke, QC; 2 Centre de Recherche Hôpital Ste Justine, Montreal, QC Objectives: The recent discovery of synthetic agonists of the CXCR4 allowed for the first time to identify potent biased ligands (ACS Med Chem Lett. 20 Aug ;2(8): ). CXCL2, the endogenous agonist ligand of CXCR4, was reputed to induce chemotaxis through CXCR4 by Gi and beta-arrestin recruitment. Synthetic full agonists with low nm affinity were produced through grafting the CXCL2 pharmacophore, its N-terminal peptide portion, onto T40, the cyclopeptide antagonist of CXCR4. Methods: Figure: Typical synthetic CXCR4 agonist with 4 nm affinity and full agonist properties on chemotaxis and Gi activation. Results: These agonists displayed chemotactic behaviour like CXCL2, both in vitro and in vivo. Subsequent signalling pathway analysis showed that these agonists couple, like CXCL2, CXCR4 to Gi with nanomolar affinities. These synthetic agonists however do not induce beta-arrestin coupling and consequently, significantly reduce CXCR4 internalization upon CXCL2 stimulation. Conclusions: The availability of biased agonists for these chemokine receptors will allow dissection of the hitherto not well-understood functional interactions of CXCR4. These agonists are also of interest as tools for structural biology investigations to provide molecular details on the mechanism of CXCR4 activation, which remains unknown despite the CXCR4 crystal structure. Finally, agonistic CXCR4 ligands possess several attractive features as alternatives for CXCR4 targeted drug therapy where antagonists are actually the only option; therefore synthetic transitions to partial and fully peptidomimetic agonistic moieties are under way. 5 - Prevalence of heavy prenatal alcohol exposure in Uganda, Africa via analysis of fatty acid ethyl esters in meconium Nightingale, Ira ; Koren, Gideon 2 ; MacLeod, Stuart 3 ; Matthew, Wiens 3 University of Toronto, Toronto, ON; 2 The Hospital for Sick Children, Toronto, ON; 3 University of British Columbia, Vancouver, BC Objectives: The focus of this study is to measure the prevalence of heavy prenatal alcohol exposure during pregnancy by meconium fatty-acid ethyl esters (FAEEs) analysis in a population-based setting. Fetal alcohol spectrum disorder (FASD) manifests a continuum of permanent birth defects and neurodevelopmental 3 P a g e

14 impairments that originate from maternal alcohol use during pregnancy. Previous literature found that of the Ugandan women who drank regularly prior to pregnancy, only 8.3% reported abstinence, whereas an astonishing.% increased alcohol use, and 68.3% decreased consumption. Thus, the number of FASD cases in parts of the sub-saharan Africa is growing, which is a cause for concern due to the socio-economic impact. Methods: Meconium samples were collected from 505 newborns between October-November 203 at Mbarara Regional Referral Hospital. Each meconium sample was accompanied with a questionnaire containing neonatal/maternal information. FAEEs are non-oxidative metabolites of ethanol produced in the fetus are serves as an established biomarker for in utero alcohol exposure. FAEE meconium concentrations greater than 2.00 nmol/g are considered indicative of heavy prenatal alcohol exposure during the last two trimesters of pregnancy. Samples were frozen and shipped to the Motherisk Laboratory for analysis. FAEEs were analyzed by gas chromatography-mass spectrometry and quantified using deuterated internal standards. Results: Of the 505 samples, 68 have been analyzed by GC/MS to date, where 2 are inconclusive due to it being transitional with stool. The remaining 66 samples did not show heavy prenatal alcohol exposure. Meconium FAEE analysis is currently ongoing at Motherisk Laboratory. Conclusions: The identification of specific populations in need of basic epidemiologic research on the prevalence of prenatal alcohol exposure is urgently required in order to create awareness and reduce the devastation of FASD. This is the first population-wide study of an entire neonatal population examining fetal alcohol exposure conducted in Uganda. 6 - Barth syndrome and the use of monolysocardiolipin acyltransferase- as a potential therapeutic agent Mejia, Edgard; Cole, Laura; Hatch, Grant; Taylor, William Manitoba Institute of Child Health, Winnipeg, MB Objectives:.) Examine the effects of tafazzin alteration in vitro and ex vivo. 2.) Determine the effects of MLCL AT- expression in healthy and BTHS lymphoblasts. Methods: Eppstein-Barr virus transformed lymphoblasts from healthy and BTHS patients were transfected with TAZ or MLCL AT- RNAi or an MLCL AT- carrying plasmid. TAZ and MLCL AT- gene expression was analyzed using RT-PCR. Mitochondrial fractions from both cell lines were used to study MLCL AT- enzyme activity. Linoleic acid incorporation into CL was also studied by using [4C] Linoleic acid and then radioactivity incorporated into CL determined. CL was also isolated from healthy and BTHS lymphoblasts and CL mass was measured using phospholipid phosphorous analysis. Blue native polyacrylamide gel electrophoresis (BN-PAGE) was used to analyze mitochondrial supercomplexes in healthy and BTHS lymphoblasts, as well as in tissues from wild-type and Taz knockdown mice. Mitochondrial function was analyzed in healthy and BTHS lymphoblasts using a Seahorse XF 24 Extracellular Flux Analyzer. Results: MLCL AT- gene expression increased when TAZ was knocked down. Expression of MLCL AT- is able to increase MLCL AT- enzyme activity and CL mass in healthy and BTHS lymphoblasts. No significant change in [4C] linoleic acid incorporation into CL was observed. Mitochondrial supercomplex formation is disturbed in BTHS lymphoblasts, however, MLCL AT- expression is able to elevate mitochondrial supercomplex (and complex I) formation in these cells. In Taz knockdown mice, supercomplex formation is also disturbed. Our results also indicate the overall disturbance of mitochondrial function in BTHS lymphoblasts, but the use MLCL AT- is able to improve this effect. Conclusions: The use of human lymphoblasts and the Taz knockdown mouse model will help us better understand the complexities of BTHS. MLCL AT- expression may serve as a potential therapeutic approach to treat BTHS. 7 - Examination of a protein kinase inhibitor library for alterations in P-glycoprotein expression and activity Pogorzelec, Michael; Habte, Ruth; Miller, Donald University of Manitoba, Winnipeg, MB Objectives: ATP Binding Cassette (ABC) transporters play a critical role in absorption, distribution and elimination of a broad range of pharmaceuticals. Little is known about potential influences of kinase pathway modulation on expression and activity of ABC transporters. The present study analyzed a PKI library 4 P a g e

15 targeting over 25 different kinases, to determine the effect on activity and expression of P-glycoprotein (Pgp) in different representative cell lines. Methods: Various cell lines, including MDCK-MDR, MDCK-wt, Caco-2 and HBMEC were grown to confluency on 96 well plates. Cells were exposed to the PKIs (2 μm) for 24 hours, and uptake studies were performed using rhodamine 23 (R23) as a fluorescent probe for P-gp. Changes in efflux activity (EA) were determined and those PKIs producing a change in EA of 25% or more were considered hits. All PKI hits in the ABC transporter activity assay were examined for alterations in protein expression, using in-cell western analysis with P-gp antibody. Results: A total of 33 out of the 360 PKIs screened in MDCK-MDR and MDCK-wt cells were identified as hits in the R23 P-gp activity assay. Nine of the 33 PKIs targeting GSK-3 resulted in an increase in P-gp EA. Only 5 of the 33 PKIs produced changes in P-gp expression in MDCK. The 33 PKI hits were also examined in Caco-2 and HBMEC cell lines. Only one and five of the 33 PKIs were identified as hits in Caco- 2 and HBMEC, respectively. None of the hits from the R23 accumulation assay significantly altered P-gp expression in Caco-2 and HBMEC. Conclusions: PKIs influenced P-gp activity in a cell line dependent manner. In many instances, changes in P-gp activity were not associated with changes in expression levels. Funding provided by NSERC Canada. 8 - In vitro functional analysis of novel single nucleotide polymorphisms in OATPB Zhiyuan, Yin; Kim, Richard Western University, London, ON Objectives: Statin-induced myopathy is a common adverse reaction experienced by patients on statin therapy. Patients who exhibit elevated plasma concentration of statins are thought to be at a greater risk for myopathy. Statins are transported from the blood to hepatocytes via organic anion transporting polypeptide B (OATPB). Single nucleotide polymorphisms (SNPs) in OATPB, primarily OATPB*5, have been shown to affect plasma statin concentrations. We hypothesized that there may be other SNPs in OATPB that can also contribute to reduced transport activity and increased plasma statin levels. Methods: OATPB cdna packaged in pef6/v5-his TOPO was used as template, and 6 SNPs 298G>A (rs ), 49C>T (rs ), 463C>A (rs04589, *4), 007C>G (rs ), 463G>C (rs , *9), and 738C>T (rs75894) were introduced separately to wild-type templates using site-directed mutagenesis. OATPB variant cdnas were expressed in adenovirus. Transport activity was measured with prototypical substrates estrone-3-sulfate, estradiol-7-β-d-glucuronide, and rosuvastatin. Results: Total uptake was decreased in 49C>T variant, increased in 007C>G variant, unchanged in *4 variant, and completely abolished in 298G>A, *9, and 738C>T variants compared to wildtype. Kinetic experiments showed a decrease in Vmax in 49C>T and *4 and an increase in Vmax in 007C>G with all 3 substrates. Kinetic parameters could not be calculated for variants 298G>A, *9, and 738C>T because of near complete absence of transport activity. Western blots showed total cellular expression of OATPB was slightly decreased in 298G>A, 49C>T, *9, and 738C>T, and slightly increased in 007C>G compared to wildtype. Cell-surface fraction analysis also showed a similar trend. Conclusions: Our data support the hypothesis that there are additional loss of function SNPs in OATPB. Additional clinical validation studies are ongoing. We also plan on carrying out Next-gen sequencing OATPB among patients who exhibit significantly higher than expected statin levels which are not explained by the currently known SNPs in this transporter. 9 - A novel ethambutol prodrug to optimize drug delivery to the central nervous system for the treatment of tuberculosis meningitis Pinto, Leonardo ; Bapat, Priya ; Koren, Gideon ; Peccinini, Rosângela 2 The Hospital for Sick Children, Toronto, ON; 2 Universidade Estadual Paulista Julio de Mesquita Filho, Araraquara, Sao Paulo, Brazil Objectives: The objectives of this study were to synthesize and structurally characterize a new ethambutol prodrug (ETB-CDS) using a Chemical Delivery System to improve the kinetic disposition of ethambutol for the treatment of tuberculosis meningitis (TM). We evaluated antimycobacterial and hydrolysis activities of ETB-CDS, and compared the pharmacokinetics profiles of ETB and ETB-CDS in rats. 5 P a g e

16 Methods: Ethambutol (ETB) was covalently linked to nicotinic acid using dicyclohexylcarbodiimide as a coupling agent. The reaction product was then quaternized with methyl iodide to generate the pyridinium salt. The final step was the reduction of pyridinium moiety using sodium ditionite to produce ETB-CDS. All synthesized compounds were characterized and analyzed structurally by FTIR, C3NMR, HNMR spectroscopy. The minimal inhibitory concentration (MIC) of ETB-CDS against M. tuberculosis H37Rv (ATTC 27294) was determined using a Microplate Alamar Blue Assay. Chemical and enzymatic hydrolysis studies of ETB-CDS were carried out using acetate and phosphate buffer solutions and human plasma over 24 hours (ph.2 and 7.4, respectively). Male Wistar rats (n=40) received either ETB (25 mg/kg) or ETB- CDS (25 mg/kg) via intravenous administration. Serial blood samples were collected for 20 minutes following drug administration. ETB and ETB-CDS plasma concentrations were determined by HPLC with electrochemical and UV-Vis detection, respectively. Results: ETB-CDS was synthesized with global yields of 0.7% and its structure was identified using spectral data. The prodrug inhibited M. tuberculosis growth with a MIC of 3.25 µg/ml and had a higher partition coefficient than the parent drug. ETB-CDS remained stable at different phs in the chemical and enzymatic assays. Compared to ETB, ETB-CDS demonstrated a slower clearance (20 vs 75 ml/min/kg, p<0.05) and longer elimination half-life (.6 vs 33.3 min, p<0.05). ETB-CDS had a larger AUC [0- ] (296.6 vs 30.5 µg/ml/min, p<0.05), and larger Vd than ETB (6.2 vs 3.6 L/Kg, p<0.05). Conclusions: Our results suggest that ETB-CDS can be a promising candidate for the treatment of TBM. ETB-CDS has a lipophilic pharmacokinetic profile, which may improve its ability to penetrate the blood-brain barrier. 0 - Evaluating the transfer mechanism of rivaroxaban across the dually perfused human placenta Bapat, Priya ; Pinto, Leonardo ; Lubetsky, Angelika ; Melamed, Nir ; Berger, Howard 2 ; Koren, Gideon Hospital for Sick Children, Toronto, ON; 2 St. Michael's Hospital, Toronto, ON Objectives: The objectives of our study were to determine the transplacental pharmacokinetics at term of the oral anticoagulant, rivaroxaban, in order to estimate fetal drug exposure, and determine if passive diffusion was the primary mechanism of rivaroxaban transfer across the human placenta. Methods: Placentae were obtained with informed consent after caesarean delivery of uncomplicated term pregnancies. The transplacental pharmacokinetics of rivaroxaban were measured using dual perfusion of an isolated placental lobule ex vivo. Rivaroxaban, at a concentration of 250 ng/ml, was added to the maternal or fetal circulation only and samples were taken during the pre-experimental ( h) and experimental (3 h) phases for measurement of rivaroxaban and markers of placental viability. Additional perfusions were conducted under equilibrative conditions with the addition of rivaroxaban to the maternal and fetal circulations at a concentration of 250 ng/ml. Rivaroxaban levels were detected using liquid chromatographymass spectrometry (LC/MS). Results: There was rapid transfer of rivaroxaban across the human placenta in both the maternal-to-fetal and fetal-to-maternal directions, as evidenced by transfer ratios of 0.72 ± 0.2 (n=5) and 0.69 ± 0.03 (n=2) after 3 hours. Under equilibrative conditions, rivaroxaban concentrations remained relatively constant, suggesting that rivaroxaban crosses the placenta down a concentration gradient. Placental viability markers remained within normal physiological ranges. Conclusions: This is the first direct evidence of rapid transfer of rivaroxaban across the human placenta from the mother to fetus and fetus to mother. The results suggest that rivaroxaban crosses the placental barrier via passive diffusion. - Cisplatin nephrotoxicity in Mexican children with solid tumors Carleton, Bruce ; Jimenez, Ricardo ; Rassekh, Rod 2 ; Jiménez-Triana, Climaco 3 ; Rivas, Rodolfo 3 ; Medina, Aurora 3 ; Daniel, Castelán 3 ; Medeiros, Mara 3 University of British Columbia, Vancouver, BC; 2 British Columbia Children's Hospital, Vancouver, BC; 3 Hospital Infantil de Mexico Federico Gomez, Mexico, DF Objectives: To evaluate the prevalence and severity of cisplatin nephrotoxicity in Mexican children and too determine the impact of nephrotoxicity in growth. Methods: Retrospective study in 5 children treated with cisplatin for solid tumors. From the clinical chart the information about height, serum creatinine and electrolytes in each cisplatin cycle and after 2 months of treatment was recorded. Nephrotoxicity was graded as follows, 0: normal renal function, : asymptomatic 6 P a g e

17 electrolytes disorders in blood work, grade 2: need for electrolyte supplementation and/or increase in serum creatinine.5-.9 times from baseline, grade 3: increase in serum creatinine times from baseline or need for electrolyte supplementation for more than 3 months after treatment completion, grade 4: renal replacement therapy. Results: 38 patients had nephrotoxicity NTX- (74.5%). Hypophosphatemia was found in 34 patients, hypomagnesemia in 2, hypokalemia in 8 patients. Grade NTX was observed in 6 and Grade 2 in 22. NTX patients were younger than patients with no-ntx (mean age 6. ± 4.5 years vs..52 ± 5.4 respectively, p=0.00), received higher cisplatin total dose (mean accumulated dose in NTX 455mg/m2 vs. 372mg/m2 in no-ntx, p=0.0). There was no change in z Score for height (baseline vs. 2 months) in no- NTX patients, NTX Grade had a significant worsening of the height (z Score baseline -0.39± 0.2 vs. -. ±0.3, paired t test p=0.006), Grade 2 non-significant (p=0.056). We found a negative significant correlation between cisplatin total dose and serum magnesium levels at 2 months (Spearman r=-0.52, p=0.003). Conclusions: NTX prevalence was 74.5%. NTX patients were younger and received higher cisplatin dose than those with normal renal function. Patients with untreated electrolyte anomalies (NTX Grade ) had a significant worsening of height z Score at 2 months. 2 - Risks of congenital malformations in offspring exposed to valproic acid in utero: Emergence of the signals over the last 30 years Tanoshima, Miki; Tanoshima, Reo; Kobayashi, Tohru; Beyene, Joseph; Koren, Gideon; Uleryk, Elizabeth; Ito, Shinya The Hospital for Sick Children, University of Toronto, Toronto, ON Objectives: Over the last 30 years, valproic acid (VPA) has been suspected as a human teratogen, based on reports of case-control and cohort studies. Since 2009, three large-scale registry-based studies reported significant association between VPA exposure in utero and the increased risk of major congenital malformations (major CMs) including open neural tube defects. The recent surge of data quantity prompted us to systematically analyze the published data to address: ) time profiles of emergence of the VPA teratogenicity signals over the last 30 years; and 2) risk estimates of specific CMs associated with VPA. Methods: A systematic literature search was conducted on Medline, Embase classics plus Embase, and Cochrane Central Register of Controlled Trials between 946 to November 203. The search terms were regarding congenital malformations, pregnancy, and valproic acid. Cumulative and conventional metaanalyses were performed with EZR version.2. Pooled relative risk (RR) and 95% confidence intervals of VPA monotherapy-associated risks of major CMs, compared to other antiepileptics, were calculated with fixed effects models. Results: We identified 55 cohort studies. Cumulative meta-analyses showed that the risk of combined major CMs has been statistically significant since 990. Signals of significant risks of specific major CMs (neural tube defects, congenital heart defects, cleft lip/palate, genitourinary anomalies and musculoskeletal defects) all emerged between 992 and Conventional meta-analyses showed that RR of VPA-associated major CMs were 2 to 7 fold, compared to the patients with other antiepileptic drug exposure. Sensitivity analyses confirmed the stability of the results. Conclusions: The risk signals of major CMs associated with VPA became significant more than 0 years ago. VPA exposure in utero poses 2 to 7 fold increased risks of major CMs, compared to the other antiepileptic drugs exposure. 3 - Profound reduction in the tamoxifen active metabolite endoxifen in a patient on phenytoin for epilepsy compared to a CYP2D6 genotype matched cohort Gryn, Steven; Kim, Richard; Teft, Wendy Western University, London, ON Objectives: Tamoxifen is a prodrug, requiring cytochrome P450 enzyme-mediated metabolism to form the active metabolite endoxifen. Our Personalized Medicine clinic assessed a 49-year-old woman, genotyped as a cytochrome P450 2D6 (CYP2D6) extensive metabolizer, chronically taking phenytoin for a seizure disorder, who initiated tamoxifen therapy two months prior for estrogen receptor positive breast cancer. Phenytoin would be expected to induce the metabolism of tamoxifen, although there are no previous data demonstrating the ultimate effect on endoxifen levels. We sought to determine whether such a drug-drug 7 P a g e

18 interaction would be detrimental by measuring endoxifen and intermediate metabolites in this patient, compared to other patients from our clinic matched for genotype and clinical variables. Methods: Tamoxifen and metabolite levels including endoxifen levels were measured by liquid chromatography mass spectrometry/mass spectrometry for all patients seen in our clinic taking tamoxifen, expected to be at steady state. The levels measured for the patient taking phenytoin were compared to all patients with a CYP2D6 extensive metabolizer genotype (n=95), and to patients matched for CYP2D6 */*4 genotype as well as age, height, and weight (n=8). Results: The patient had an endoxifen level of 4.7 nmol/l, the lowest our clinic has seen in an extensive metabolizer, and 6-fold lower than the median of the matched controls. Tamoxifen and intermediate metabolite ratios were also reduced, although to a lesser degree compared to the matched controls, suggesting alteration in pharmacokinetics, and not lack of compliance, led to the reduced endoxifen level. Conclusions: To our knowledge, this is the first report documenting the consequences of induction in terms of both tamoxifen and endoxifen levels during concomitant phenytoin therapy, and this effect would likely result in loss of therapeutic benefit from tamoxifen. Phenytoin should therefore not be used concurrently with tamoxifen for extended periods of time unless a therapeutic drug (endoxifen) monitoring strategy is utilized. 4 - The role of equilibrative nucleoside transporter 3 (ENT3) in regulating adenosine levels within brain Roberts, Lauren; Jackson, Michael F.; Lavine, Natalie; Xiong, Wei; Parkinson, Fiona University of Manitoba, Winnipeg, MB Objectives: Adenosine is a signaling molecule acting via cell surface G-protein coupled receptors. In brain, adenosine has neuroprotective, anticonvulsant and sedative properties. However, the mechanisms which regulate adenosine concentrations are poorly understood. Four members of the equilibrative nucleoside transporter family have been identified (ENT-4) where ENT and 2 have been best characterized to date. The current study was initiated to explore the role of ENT3 in regulating adenosine levels. Methods: Mouse ENT3 gene sequence was inserted into pires puro-flag plasmid. HEK293T cells were transiently transfected then used for western blot analysis with a commercial ENT3 specific antibody and an antibody specific for the flag epitope. Mouse brain was dissected and mrna was isolated from cortex, cerebellum, striatum and hippocampus. Reverse transcriptase polymerase chain reaction (RT-PCR) was performed using ENT3 specific primers designed to amplify a 245 bp product. The ENT3 specific antibody was used in western blot analysis of proteins isolated from the dissected regions of mouse brain. Rat C6 glioma cells, stably transfected with ENT3 or with vector alone, were exposed to hypoxic conditions and extracellular adenosine levels were quantified. Results: Western blot analysis performed using ENT3-transfected and wild type HEK293T cells showed a 40kD band in transfected cells only that was detected with either the ENT3 specific or the anti-flag antibody. RT-PCR analysis was positive for expression of ENT3 in all brain regions tested.western blot analysis of dissected mouse brain regions, using the ENT3-specific antibody, showed a major band at 52kD and a minor band of 30kD. Preliminary results indicate that ENT3 transfected C6 glioma cells released less adenosine in hypoxic conditions than vector transfected cells. Conclusions: Our results indicate that ENT3 is widely expressed in mouse brain and preliminary results indicate a role for ENT3 in intracellular sequestration of adenosine in hypoxic conditions. 5 - Clinical & Molecular Determinants for Optimal Factor Xa Inhibitor Therapy Gulilat, Marcus; Kim, Richard Western University, London, ON Objectives: Oral anticoagulants (OACs) are important to stroke prevention for patients with atrial fibrillation. Suboptimal anticoagulation can place patients at risk for a thrombotic event, while excessive anticoagulation can result in serious to fatal bleeding events. Although warfarin had been the main drug of choice for anticoagulation, newer agents that do not require routine monitoring of anticoagulation efficacy are now widely prescribed. Rivaroxaban and apixaban, belong to a new generation of Factor Xa inhibitors (FXIs) that have been approved as alternate therapies to warfarin. However, outside of clinical trials, interpatient variation in OAC blood level or the extent of Factor Xa inhibition has not been assessed. Therefore the objectives of this study are to examine the extent of interpatient variability in the plasma concentration 8 P a g e

19 rivaroxaban in patients on this agent, to better delineate the role of clinical as well as pharmacogenetic variables as determinants for identifying patients at risk for excessive as well as subtherapeutic response to these newer OACs. Methods: We assessed rivaroxaban level in n = 33 patients who were seen in our anticoagulation clinic. Rivaroxaban levels were measured using liquid chromatography-tandem mass spectrometry. Factor Xa activity was measured using the Biophen Direct Factor Xa Inhibitor (DiXaI) assay. Pharmacogenetic testing for CYP enzymes and transporters will be carried out using TaqMan SNP genotyping assay. Results: Substantial interpatient variation was observed. Forty-two percent of patients exhibited rivaroxaban level > 95% confidence interval. The pharmacological effect of FXIs is closely correlated to their blood levels. Conclusions: There is far greater variation in the observed plasma level of FXIs than currently realized. As we enroll additional patients into our study for rivaroxaban as well as apixaban, genetic variation in drug metabolizing enzymes and transporters that predict decreased or increase systemic drug exposure to these agents will also be more fully clarified. 6 - Regulation of multidrug transporter (BCRP/ABCG2) expression in the mammary gland during lactation Wu, Alex; Dalvi, Pooja; Yang, Mingdong; Turinsky, Andrei; Wang, Kelvin; Butcher, Darci; Egan, Sean; Weksberg, Rosanna; Brudno, Michael; Harper, Patricia; Ito, Shinya SickKids Research Institute, Toronto, ON Objectives: The multidrug transporter ABCG2 is upregulated in the lactating mammary gland where it concentrates drugs/toxins into breast milk. However, the mechanism for this induction is not well understood. Here we sought to explore the role of epigenetics and STAT5 in the regulation of Abcg2 in the lactating mouse mammary gland. Methods: The expression profile of Abcg2 mrna isoforms (Ea, Eb, and Ec) in the mouse mammary gland was examined using quantitative RT-PCR. Promoter DNA methylation status was assessed by bisulfite pyrosequencing. Published ChIP-seq datatsets were used to identify regions along the Abcg2 gene that was enriched with the open chromatin histone mark H3K4me2 or bound by the transcription factor STAT5 in the lactating mammary gland. STAT5 recruitment to the mouse Abcg2 gene was further assessed using a forced weaning mouse model in which pups were removed from the lactating mother to quickly turn off STAT5 activity in the mammary gland. These STAT5-binding regions were also investigated for prolactin-induced enhancer activity using luciferase reporter assays. Results: The Eb isoform was the major isoform expressed in the mouse mammary gland and was induced during lactation. The Eb promoter was hypomethylated and marked with H3K4me2 in both the virgin and lactating mammary gland. However, the Eb/Ec promoter region was more enriched with H3K4me2 during lactation. STAT5 was bound to five regions along the Abcg2 gene during lactation. The recruitment of STAT5 to these regions was significantly reduced after forced weaning. At least one of these STAT5 binding regions, which contain a putative gamma interferon-activated sequence (GAS) motif, was responsive to prolactin treatment. Conclusions: The mouse Abcg2 gene is already poised for expression in the virgin mammary gland. Therefore, the upregulated expression of Abcg2 in the mammary gland during lactation is likely due to the recruitment of activated STAT5 to the Abcg2 gene. 7 - Steady-state folate pharmacokinetics in pregnancy: A randomized clinical trial in pregnant women supplementing with.mg vs. 5mg folic acid Shere, Mahvash; Nguyen, Patricia; Tam, Carolyn; Stern, Seth; Kapur, Bhushan; O'Connor, Deborah; Koren, Gideon The Hospital for Sick Children, Toronto, ON Objectives: Folic acid supplementation during the periconceptional period reduces the risk of neural tube defects. While current prenatal recommendations are based on studies in non-pregnant women of childbearing age, this is the first study aiming to assess steady-state periconceptional and gestational RBC and plasma folate levels in pregnant women supplementing daily with prenatal multivitamins containing.mg (regular dose) vs. 5mg (high dose) folic acid. 9 P a g e

20 Methods: 37 women, between 8-45 years of age, who were early in pregnancy or trying to conceive, and were not previously taking folic acid-containing supplements, were enrolled in this open-label, 2-arm, randomized clinical trial after obtaining informed consent. Participants were randomized to take either.mg or 5mg of folic acid-containing prenatal multivitamins daily till 30 weeks gestational age (g.a.). Plasma and RBC folate levels were measured at baseline, and at g.a.6, g.a.2 and g.a.30 using a chemiluminescent immunoassay. Results: RBC folate levels significantly increased in both groups from baseline during pregnancy (p<0.0005). In the 5mg group, RBC folate levels significantly increased over the course of pregnancy between g.a.6 and g.a.30 (p<0.000), and between g.a.2 and g.a.30 (p<0.00). In the.mg group, RBC folate levels increased significantly only between g.a.2 to g.a.30 (p<0.05). Plasma folate levels increased in both groups from baseline to g.a.6, and then decreased over the course of pregnancy between g.a.6 and g.a.30, but the decrease was not statistically significant. Plasma levels at g.a.30 in both groups were comparable to their respective baseline levels. Conclusions: Pregnancy-related physiological changes in folate distribution, metabolism and elimination likely influence steady-state pharmacokinetics of folic acid. Despite supplementation over an extended period of time, steady-state does not seem to be achieved in either dose group. Moreover, the decrease in plasma folate in pregnancy may have clinical relevance for women with poor folate status, and may reflect the increased folate demands during pregnancy. 8 - A case report of warfarin and carbamazepine drug interaction Ziada, Ahmed; Kim, Richard; Schwarz, Ute; Tirona, Rommel; Morgan, Sara London Health Sciences Center, London, ON Objectives: To demonstrate the importance of considering carbamazepine and warfarin drug interaction when predicting warfarin dosing, and why the effect should not be underestimated when challenges present in attaining therapeutics INRs for these patients. Methods: Warfarin is the most frequently prescribed anticoagulant worldwide, and is known to be highly efficacious in the prevention and management of thromboembolisms. Drug interactions remain a challenge in managing patients that require warfarin therapy. Many of these interactions are a result of induction or inhibition enzymes involved in warfarin metabolism. Carbamazepine widely prescribed for epilepsy as well as chronic pain. We report the case of a 44-year-old prescribed warfarin after receiving mechanical mitral and aortic valves three months prior to being assessed by our team. Patient is also on carbamazepine CR 200 mg/day for seizure control. She showed warfarin resistance, as demonstrated by repeated subtherapeutic INR values. Her observed warfarin maintenance dose of 3 mg/day was significantly higher than the predicted dose 6 mg/day using our genomics-guided dosing nomogram. We then measured S and R warfarin plasma levels. Despite her higher than predicted warfarin dose, her measured S-warfarin levels were within the expected therapeutic range for someone with her VKORC genotype. Since INR values were in the target range, it would appear that the higher than predicted dose of warfarin was required to maintain a therapeutically relevant S and R-warfarin levels. The observed phenomenon is consistent with induction of both CYP2C9 and CYP3A4 by carbamazepine. Results: This patient s S-warfarin levels fall within the expected therapeutic range for someone with her VKORC genotype and AF indication. Since INR values were in the target range, it would seem that the cause of warfarin resistance has a pharmacokinetic origin. The therapeutic drug levels at higher than predicted dose indicates S-warfarin clearance is increased. Conclusions: Our case illustrates the importance of integrating induction-related drug interactions, as well as pharmacogenomic parameters for optimal warfarin dosing, and such patients may require far higher than predicted dose of warfarin to attain therapeutic benefit. 9 - Methadone pharmacokinetics in an obese patient Kapur, Bhushan; Lala, Prateek The Hospital for Sick Children, Toronto, ON Objectives: Patients in methadone maintenance treatment (MMT) programs frequently report recurrent withdrawal symptoms and request dose readjustment. Measuring methadone blood levels and half-life (t½) can assist physicians in evaluating if dosing adjustments are warranted. We observed that as patient weight 20 P a g e

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