Medicine and Health Sciences Commons^™

Share Cannabidiol Exposure During Gestation Leads To Adverse Cardiac Outcomes Early In Postnatal Life In Male Rat Offspring., Daniel B. Hardy, Steven R. Laviolette, Kendrick Lee, David Rc Natale

Physiology and Pharmacology Publications

Introduction: Studies indicate that *7% of pregnant individuals in North America consume cannabis in pregnancy. Pre-clinical studies have established that maternal exposure to D9-tetrahydrocannabinol (THC; major psychoactive component in cannabis) leads to fetal growth restriction and impaired cardiac function in offspring. However, the effects of maternal exposure to cannabidiol (CBD; major non-euphoric constituent) on cardiac outcomes in offspring remain unknown. Therefore, our objective is to investigate the functional and underlying molecular impacts in the hearts of offspring exposed to CBD in pregnancy. Methods: Pregnant Wistar rats were exposed to either 3 or 30mg/kg CBD or vehicle control i.p. daily from …

Cannabidiol Exposure During Rat Pregnancy Leads To Labyrinth-Specific Vascular Defects In The Placenta And Reduced Fetal Growth, Daniel B. Hardy, David R C Natale, Kendrick Lee

Physiology and Pharmacology Publications

Introduction: Cannabis use is increasing among pregnant people, and cannabidiol (CBD), a constituent of cannabis, is often perceived as ‘‘natural’’ and ‘‘safe’’ as it is non-intoxicating. In utero, cannabis exposure is associated with negative health outcomes, including fetal growth restriction (FGR). The placenta supplies oxygen and nutrients to the fetus, and alterations in placental development can lead to FGR. While there has been some investigation into the effects of D9-THC, there has been limited investigation into the impacts of in utero gestational CBD exposure on the placenta. Methods: This study used histological and transcriptomic analysis of embryonic day (E)19.5 rat …

Adverse Effects And Pharmacokinetic Characteristics Of High-Dose Glucocorticoid Treatment In Children With Rheumatic Diseases, Renee X. Pang

Electronic Thesis and Dissertation Repository

This integrated-article thesis explores the impact of long-term glucocorticoid (GC) therapy on children with RD. Long-term GC treatment is potentially associated with severe adverse drug reactions (ADRs). Our scoping review summarizes the current evidence health-related quality of life (HRQOL) impacts of this treatment on children with RD. We describe the frequency of ADRs related to long-term GC treatment in a convenience sample of pediatric RD patients on long-term prednisone therapy and evaluate clinical characteristics that may be associated with risk for of GC-related ADRs. Lastly, we present a pilot study to evaluate the feasibility of monitoring GC PK in children …

Metabolomic Approach For Earlier Diagnosis Of Cisplatin-Induced Acute Kidney Injury, Steven Xiu, James (Yong Jin) Lim

Undergraduate Student Research Internships Conference

Cisplatin is a chemotherapeutic agent complicated by its dose-limiting nephrotoxicity. This commonly presents as acute kidney injury (AKI), which is characterized by a reversible decline in kidney function. AKI is currently diagnosed by increased serum creatinine (SCr) levels, but this rise in SCr is delayed limiting diagnosis to when significant renal damage has already occurred. Currently, there are no known biomarkers capable of predicting or diagnosing early-stage cisplatin-induced AKI. Metabolomics was used to identify novel predictive/early diagnostic biomarkers for cisplatin-induced AKI. We hypothesized that differences in metabolic profiles will be able to predict and/or diagnose cisplatin-induced AKI prior to rise …

Methodological Challenges In Pharmacoeconomic Submissions For Cancer Drug Reimbursement In Canada From 2019-2021, Nupur Krishnan

Undergraduate Student Research Internships Conference

Cancer is the leading cause of death in Canada, carrying a mortality rate of 1 in 4 Canadians. As new therapeutic options are developed, high drug costs place a huge burden on patients and the healthcare system. Due to budget limitations, not all pharmaceuticals can be publicly funded, so difficult decisions must be made for which drugs are funded and in what contexts. The pan-Canadian Oncology Drug Review (pCODR) evaluates submissions for new oncological pharmaceuticals to make reimbursement recommendations. Comprehensive analyses assessing limitations in recent oncology drug submissions have not yet been performed. The objective of this project, therefore, was …

Cost-Effectiveness Analysis Of Tpmt Genotype-Guided Azathioprine Treatment Compared To Standard Treatment For Patients With Moderate/Severe Ulcerative Colitis, Ali Unsal

Electronic Thesis and Dissertation Repository

This study assessed cost-effectiveness of pharmacogenomics (PGx)-based azathioprine (AZA) compared to standard AZA therapy for ulcerative colitis (UC) patients in Canada. A patient-level Microsimulation model was developed to compare the lifetime costs and quality-adjusted life years (QALYs) gained by a hypothetical cohort of UC patients with age and sex characteristics. The parameters used in the model were derived from the published literature and costs from the Ontario Schedules of Payments and published sources. The results were summarized in terms of the incremental cost-effectiveness ratio (ICER). Compared to standard AZA, PGx-based AZA care was the dominant strategy with 0.17 incremental QALYs …

Effects Of Annexin A5 On Endothelial Inflammation Induced By Lipopolysaccharide-Activated Platelets And Extracellular Vesicles, Brent Jeffrey Tschirhart

Electronic Thesis and Dissertation Repository

Sepsis is a dysregulated immune response to infection and the leading cause of mortality globally, accounting for 11 million deaths in 2017. To date, no therapeutics are available to treat the underlying septic response. Previous research from our laboratory has shown that annexin A5 (Anx5) treatment increased survival by 40% in mice with endotoxemia, a model of sepsis. During sepsis, activated platelets release membrane fragments called extracellular vesicles (EVs) with externalization of phosphatidylserine to which annexin A5 binds with a high affinity. We hypothesized that annexin A5 will block the pro-inflammatory response induced by activated platelets and EVs in vascular …

Exogenous Surfactant As A Delivery Vehicle For Intrapulmonary Therapeutics, Brandon J. Baer

Electronic Thesis and Dissertation Repository

As an organ system, the lung has unique advantages and disadvantages for direct drug delivery. Its contact with the external environment allows for the airways to be easily accessible to intrapulmonary delivery. However, its complex structure, which divides into more narrow airways with each branch, can make direct delivery to the remote alveoli challenging. The objective of this thesis was to overcome this issue by using exogenous surfactant, a lipoprotein complex used to treat neonatal respiratory distress syndrome, as a carrier for pulmonary therapeutics. It was hypothesized that therapeutics administered with a surfactant vehicle would display enhanced delivery to the …

Point Substitutions In G Protein-Coupled Receptors, Jessica Brown

Undergraduate Student Research Internships Conference

G protein-coupled receptors (GPCRs) are proteins that are important in physiological regulatory processes within the body, and for this reason are important drug targets. When bound to an agonist, such as neurotransmitters or hormones, the receptor adopts an active state to allow these biochemical pathways to occur. However, mutations can arise within the receptor that affect its ability to bind its agonist. This natural variation found within the genome can make it difficult to design pharmaceuticals to target the receptors.

To see the effects of these point substitutions on agonist-induced receptor activation, mutations were made within a negative allosteric site …

Impact Of Clinical And Pharmacogenetic Variables On The Risk Of Fluoropyrimidine-Related Adverse Events Within Ontario, Theodore J. Wigle

Electronic Thesis and Dissertation Repository

Severe life-threatening adverse events are a major limitation of fluoropyrimidine chemotherapy, these events are disastrous for patients and costly to the healthcare system. Identifying patients at high risk for developing adverse events would allow for preventive dose reduction, improving patient outcomes and reducing healthcare cost. This thesis uses data pulled from provincial databases to quantify the adverse event burden of fluoropyrimidines in Ontario. We found that 31% of Ontario patients treated with fluoropyrimidine systemic chemotherapy developed a severe adverse event that requires acute medical care. Patients that required acute medical therapy were significantly costlier to the public system averaging an …

Fall Risk-Increasing Drugs And Gait Performance In Community-Dwelling Older Adults: Results From The Gait And Brain Study, Abdelhady Osman

Electronic Thesis and Dissertation Repository

Medication use and gait impairment are two of the most important risk factors for falls. Several drug classes have been classified as fall risk-increasing drugs (FRIDs). Gait is an important marker of overall health and independence in older adults. The overall aim of this thesis was to examine the relationship between FRIDs and gait performance in older adults through two studies. Firstly, our systematic review of twenty studies on the association between FRIDs and gait performance found that the use of drugs with sedative properties is associated with reduced gait speed. Secondly, we conducted a cross-sectional analysis of data from …

Critically Ill Covid-19 Patients Exhibit Anti-Sars-Cov-2 Serological Responses, Mark Daley, Douglas D. Fraser, Gediminas Cepinskas, Marat Slessarev, Claudio M. Martin, Maitray A. Patel, Michael Miller, Eric K. Patterson, David B. O’Gorman, Sean E. Gill, Ian Higgins, Julius P. John, Christopher Melo, Lylia Nini, Xiaoqin Wang, Johannes Zeidler, Jorge A. Cruz-Aguado

Physiology and Pharmacology Publications

Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, is a global health care emergency. Anti-SARS-CoV-2 serological profiling of critically ill COVID-19 patients was performed to determine their humoral response. Blood was collected from critically ill ICU patients, either COVID-19 positive (+) or COVID-19 negative (−), to measure anti-SARS-CoV-2 immunoglobulins: IgM; IgA; IgG; and Total Ig (combined IgM/IgA/IgG). Cohorts were similar, with the exception that COVID-19+ patients had a greater body mass indexes, developed bilateral pneumonias more frequently and suffered increased hypoxia when compared to COVID-19-patients (p < 0.05). The mortality rate for COVID-19+ patients was 50%. COVID-19 status could be determined by anti-SARS-CoV-2 serological responses with excellent classification accuracies on ICU day 1 (89%); ICU day 3 (96%); and ICU days 7 and 10 (100%). The importance of each Ig isotype for determining COVID-19 status on combined ICU days 1 and 3 was: Total Ig, 43%; IgM, 27%; IgA, 24% and IgG, 6%. Peak serological responses for each Ig isotype occurred on different ICU days (IgM day 13 > IgA day 17 > IgG persistently increased), with the Total Ig peaking at approximately ICU day …

The Role Of Panx3 In Age-Associated And Injury-Induced Intervertebral Disc Degeneration, Meaghan Serjeant, Paxton M. Moon, Diana Quinonez, Silvia Penuela, Frank Beier, Cheryle A. Séguin

Physiology and Pharmacology Publications

© 2021 by the authors. Licensee MDPI, Basel, Switzerland. Pannexin 3 (Panx3) is a mechanosensitive, channel-forming glycoprotein implicated in the progression of post-traumatic osteoarthritis. Despite evidence for Panx3 expression in the intervertebral disc (IVD), its function in this cartilaginous joint structure remained unknown. Using Panx3 knockout mice, this study investigated the role of Panx3 in age-associated IVD degeneration and degeneration induced by annulus fibrosus (AF) needle puncture. Loss of Panx3 did not significantly impact the progression of age-associated histopathological IVD degeneration; however, loss of Panx3 was associated with decreased gene expression of Acan, Col1a1, Mmp13 and Runx2 and altered localization …

Are We Missing The Target? Are We Aiming Too Low? What Are The Aerobic Exercise Prescriptions And Their Effects On Markers Of Cardiovascular Health And Systemic Inflammation In Patients With Knee Osteoarthritis? A Systematic Review And Meta-Analysis, Jenna M. Schulz, Trevor B. Birmingham, Hayden F. Atkinson, Emilie Woehrle, Codie A. Primeau, Michael J. Lukacs, Baraa K. Al-Khazraji, Michaela C.M. Khan, Bryn O. Zomar, Robert J. Petrella, Frank Beier, C. Thomas Appleton, J. Kevin Shoemaker, Dianne M. Bryant

Physiology and Pharmacology Publications

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ. Objectives We systemically reviewed published studies that evaluated aerobic exercise interventions in patients with knee osteoarthritis (OA) to: (1) report the frequency, intensity, type and time (FITT) of exercise prescriptions and (2) quantify the changes in markers of cardiovascular health and systemic inflammation. Data sources PubMed, CINAHL, Scopus; inception to January 2019. Eligibility criteria Randomised clinical trials (RCT), cohort studies, case series. Design We summarised exercise prescriptions for all studies and calculated effect sizes with 95% CIs for between-group (RCTs that compared exercise and …

Inflammation Profiling Of Critically Ill Coronavirus Disease 2019 Patients., Douglas D Fraser, Gediminas Cepinskas, Marat Slessarev, Claudio Martin, Mark Daley, Michael R Miller, David B O'Gorman, Sean E Gill, Eric K Patterson, Claudia C Dos Santos

Physiology and Pharmacology Publications

Objectives: Coronavirus disease 2019 is caused by severe acute respiratory syndrome-coronavirus-2 infection to which there is no community immunity. Patients admitted to ICUs have high mortality, with only supportive therapies available. Our aim was to profile plasma inflammatory analytes to help understand the host response to coronavirus disease 2019.

Design: Daily blood inflammation profiling with immunoassays.

Setting: Tertiary care ICU and academic laboratory.

Subjects: All patients admitted to the ICU suspected of being infected with severe acute respiratory syndrome-coronavirus-2, using standardized hospital screening methodologies, had daily blood samples collected until either testing was confirmed negative on ICU day 3 (coronavirus …

Olive Oil Diet In Mild Pre-Gestational Diabetes Impacts Offspring Β-Cell Development., Bushra Taqui, Farsad Asadi, Evangelina Capobianco, Daniel Barry Hardy, Alicia Jawerbaum, Edith Juliana Arany

Physiology and Pharmacology Publications

Maternal diabetes impairs fetal development and increases the risk of metabolic diseases in the offspring. Previously, we showed maternal dietary supplementation with 6% of olive oil prevents diabetes-induced embryo and fetal defects, in part, through the activation of peroxisome proliferator-activated receptors (PPARs). In this study we examined the effects of this diet on neonatal and adult pancreatic development in both male and female offspring. A mild diabetic model was developed by injecting neonatal rats with streptozotocin (90 mg/kg). During pregnancy these dams were fed a chow diet supplemented or not with 6% olive oil. Dual immunohistochemistry was performed to detect …

Overexpression Of Mig-6 In The Cartilage Induces An Osteoarthritis-Like Phenotype In Mice, Melina Bellini, Michael A. Pest, Manuela Miranda-Rodrigues, Ling Qin, Jae Wook Jeong, Frank Beier

Physiology and Pharmacology Publications

© 2020 The Author(s). Background: Osteoarthritis (OA) is the most common form of arthritis and characterized by degeneration of the articular cartilage. Mitogen-inducible gene 6 (Mig-6) has been identified as a negative regulator of the epidermal growth factor receptor (EGFR). Cartilage-specific Mig-6 knockout (KO) mice display increased EGFR signaling, an anabolic buildup of the articular cartilage, and formation of chondro-osseous nodules. Since our understanding of the EGFR/Mig-6 network in the cartilage remains incomplete, we characterized mice with cartilage-specific overexpression of Mig-6 in this study. Methods: Utilizing knee joints from cartilage-specific Mig-6-overexpressing (Mig-6 over/over ) mice (at multiple time points), we …

Vascular Risk Reduction In Obesity Through Reduced Granulocyte Burden And Improved Angiogenic Monocyte Content Following Bariatric Surgery., David A Hess, Justin Z Trac, Stephen A Glazer, Daniella C Terenzi, Adrian Quan, Hwee Teoh, Mohammed Al-Omran, Deepak L Bhatt, C David Mazer, Ori D Rotstein, Subodh Verma

Physiology and Pharmacology Publications

Bariatric surgery, in addition to the benefit of sustained weight loss, can also reduce cardiometabolic risk and mortality. Lifelong vessel maintenance is integral to the prevention of cardiovascular disease. Using aldehyde dehydrogenase activity, an intracellular detoxifying enzyme present at high levels within pro-vascular progenitor cells, we observed an association between chronic obesity and "regenerative cell exhaustion" (RCE), a pathology whereby chronic assault on circulating regenerative cell types can result in adverse inflammation and diminished vessel repair. We also describe that, at 3 months following bariatric surgery, systemic inflammatory burden was reduced and pro-angiogenic macrophage precursor content was improved in subjects …

Maternal Exposure To Δ9-Tetrahydrocannabinol Impairs Female Offspring Glucose Homeostasis And Endocrine Pancreatic Development In The Rat., Ryan Gillies, Kendrick Lee, Sebastian Vanin, Steven R Laviolette, Alison C Holloway, Edith Arany, Daniel B Hardy

Physiology and Pharmacology Publications

Recent reports indicate that 7% of pregnant mothers in North America use cannabis. This is concerning given that in utero exposure to Δ9-tetrahydrocannabinol (Δ9-THC), the main psychoactive component in cannabis, causes fetal growth restriction and may alter replication and survival of pancreatic β-cells in the offspring. Accordingly, we hypothesized that maternal exposure to Δ9-THC during pregnancy will impair postnatal glucometabolic health of offspring. To test this hypothesis, pregnant Wistar rats were treated with daily intraperitoneal injections of either 3 mg/kg Δ9-THC or vehicle from gestational day 6 to birth. Offspring were subsequently challenged with glucose and insulin at 5 months …

Maternal Exposure To Δ9-Tetrahydrocannabinol Impairs Female Offspring Glucose Homeostasis And Endocrine Pancreatic Development In The Rat., Ryan Gillies, Kendrick Lee, Sebastian Vanin, Steven R Laviolette, Alison C Holloway, Edith Arany, Daniel B Hardy

Physiology and Pharmacology Publications

Recent reports indicate that 7% of pregnant mothers in North America use cannabis. This is concerning given that in utero exposure to Δ9-tetrahydrocannabinol (Δ9-THC), the main psychoactive component in cannabis, causes fetal growth restriction and may alter replication and survival of pancreatic β-cells in the offspring. Accordingly, we hypothesized that maternal exposure to Δ9-THC during pregnancy would impair postnatal glucometabolic health of offspring. To test this hypothesis, pregnant Wistar rats were treated with daily intraperitoneal injections of either 3 mg/kg Δ9-THC or vehicle from gestational day 6 to birth. Offspring were subsequently challenged with glucose and insulin at 5 months …

Chronic Morphine Regulates Trpm8 Channels Via Mor-Pkcβ Signaling, Mircea Iftinca, Lilian Basso, Robyn Flynn, Charlie Kwok, Corinne Roland, Ahmed Hassan, Manon Defaye, Rithwik Ramachandran, Tuan Trang, Christophe Altier

Physiology and Pharmacology Publications

© 2020 The Author(s). Postoperative shivering and cold hypersensitivity are major side effects of acute and chronic opioid treatments respectively. TRPM8 is a cold and menthol-sensitive channel found in a subset of dorsal root ganglion (DRG) nociceptors. Deletion or inhibition of the TRPM8 channel was found to prevent the cold hyperalgesia induced by chronic administration of morphine. Here, we examined the mechanisms by which morphine was able to promote cold hypersensitivity in DRG neurons and transfected HEK cells. Mice daily injected with morphine for 5 days developed cold hyperalgesia. Treatment with morphine did not alter the expressions of cold sensitive …

Gsk3787-Loaded Poly(Ester Amide) Particles For Intra-Articular Drug Delivery, Ian J. Villamagna, Danielle M. Mcrae, Aneta Borecki, Xueli Mei, François Lagugné-Labarthet, Frank Beier, Elizabeth Gillies

Physiology and Pharmacology Publications

© 2020 by the authors. Osteoarthritis (OA) is a debilitating joint disorder affecting more than 240 million people. There is no disease modifying therapeutic, and drugs that are used to alleviate OA symptoms result in side effects. Recent research indicates that inhibition of peroxisome proliferator-activated receptor ffi (PPARffi) in cartilage may attenuate the development or progression of OA. PPARffi antagonists such as GSK3787 exist, but would benefit from delivery to joints to avoid side effects. Described here is the loading of GSK3787 into poly(ester amide) (PEA) particles. The particles contained 8 wt. % drug and had mean diameters of about …

Molecular Basis For Activation And Biased Signaling At The Thrombin-Activated Gpcr Proteinase Activated Receptor-4 (Par4), Pierre E. Thibeault, Jordan C. Lesarge, D'Arcy Arends, Michaela Fernandes, Peter Chidiac, Peter B. Stathopulos, Leonard G. Luyt, Rithwik Ramachandran

Physiology and Pharmacology Publications

© 2020 Thibeault et al. Proteinase-activated receptor (PAR)-4 is a member of the proteolytically-activated PAR family of G-protein– coupled receptors (GPCR) that represents an important target in the development of anti-platelet therapeutics. PARs are activated by proteolytic cleavage of their receptor N terminus by enzymes such as thrombin, trypsin, and cathepsin-G. This reveals the receptor-activating motif, termed the tethered ligand that binds intramolecularly to the receptor and triggers signaling. However, PARs are also activated by exogenous application of synthetic peptides derived from the tethered-ligand sequence. To better understand the molecular basis for PAR4-dependent signaling, we examined PAR4-signaling responses to a …

Δ9-Tetrahydrocannabinol Exposure During Rat Pregnancy Leads To Symmetrical Fetal Growth Restriction And Labyrinth-Specific Vascular Defects In The Placenta., Bryony V Natale, Katarina N Gustin, Kendrick Lee, Alison C Holloway, Steven R Laviolette, David R C Natale, Daniel B Hardy

Physiology and Pharmacology Publications

1 in 5 women report cannabis use during pregnancy, with nausea cited as their primary motivation. Studies show that (-)-△9-tetrahydrocannabinol (Δ9-THC), the major psychoactive ingredient in cannabis, causes fetal growth restriction, though the mechanisms are not well understood. Given the critical role of the placenta to transfer oxygen and nutrients from mother, to the fetus, any compromise in the development of fetal-placental circulation significantly affects maternal-fetal exchange and thereby, fetal growth. The goal of this study was to examine, in rats, the impact of maternal Δ9-THC exposure on fetal development, neonatal outcomes, and placental development. Dams received a daily intraperitoneal …

Quantification Of Joint Blood Flow By Dynamic Contrast-Enhanced Near-Infrared Spectroscopy: Application To Monitoring Disease Activity In A Rat Model Of Rheumatoid Arthritis, Seva Ioussoufovitch, Laura B. Morrison, Lise Desjardins, Jennifer A. Hadway, Keith St Lawrence, Ting Yim Lee, Frank Beier, Mamadou Diop

Physiology and Pharmacology Publications

No abstract provided.

Postnatal Catch-Up Growth Leads To Higher P66shc And Mitochondrial Dysfunction., Shelby Oke, Gurjeev Sohi, Daniel Barry Hardy

Physiology and Pharmacology Publications

Epidemiological data suggest an inverse relationship between birth weight and long-term metabolic deficits, which is exacerbated by postnatal catch-up growth. We have previously demonstrated that rat offspring subject to maternal protein restriction (MPR) followed by catch-up growth exhibit impaired hepatic function and ER stress. Given that mitochondrial dysfunction is associated with various metabolic pathologies, we hypothesized that altered expression of p66Shc, a gatekeeper of oxidative stress and mitochondrial function, contributes to the hepatic defects observed in MPR offspring. To test this hypothesis, pregnant Wistar rats were fed a control (20% protein) diet or an isocaloric low protein (8%; LP) diet …

Postnatal Catch-Up Growth Leads To Higher P66shc And Mitochondrial Dysfunction., Shelby Oke, Gurjeev Sohi, Daniel Barry Hardy

Physiology and Pharmacology Publications

Epidemiological data suggest an inverse relationship between birth weight and long-term metabolic deficits, which is exacerbated by postnatal catch-up growth. We have previously demonstrated that rat offspring subject to maternal protein restriction (MPR) followed by catch-up growth exhibit impaired hepatic function and ER stress. Given that mitochondrial dysfunction is associated with various metabolic pathologies, we hypothesized that altered expression of p66Shc, a gatekeeper of oxidative stress and mitochondrial function, contributes to the hepatic defects observed in MPR offspring. To test this hypothesis, pregnant Wistar rats were fed a control (20% protein) diet or an isocaloric low protein (8%; LP) diet …

Exposure To The Rxr Agonist Sr11237 In Early Life Causes Disturbed Skeletal Morphogenesis In A Rat Model, Holly Dupuis, Michael Andrew Pest, Ermina Hadzic, Thin Xuan Vo, Daniel B. Hardy, Frank Beier

Physiology and Pharmacology Publications

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Longitudinal bone growth occurs through endochondral ossification (EO), controlled by various signaling molecules. Retinoid X Receptor (RXR) is a nuclear receptor with important roles in cell death, development, and metabolism. However, little is known about its role in EO. In this study, the agonist SR11237 was used to evaluate RXR activation in EO. Rats given SR11237 from post-natal day 5 to post-natal day 15 were harvested for micro-computed tomography (microCT) scanning and histology. In parallel, newborn CD1 mouse tibiae were cultured with increasing concentrations of SR11237 for histological and whole-mount evaluation. …

Drug Interactions And Pharmacogenetic Factors Contribute To Variation In Apixaban Concentration In Atrial Fibrillation Patients In Routine Care, Markus Gulilat, Denise Keller, Bradley Linton, A. Demetri Pananos, Daniel Lizotte, George K. Dresser, Jeffrey Alfonsi, Rommel G. Tirona, Richard B. Kim, Ute I. Schwarz

Physiology and Pharmacology Publications

Factor Xa-inhibitor apixaban is an oral anticoagulant prescribed in atrial fibrillation (AF) for stroke prevention. Its pharmacokinetic profile is known to be affected by cytochrome P450 (CYP)3A metabolism, while it is also a substrate of the efflux transporters ATP-binding cassette (ABC)B1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein, BCRP). In this study, we assessed the impact of interacting medication and pharmacogenetic variation to better explain apixaban concentration differences among 358 Caucasian AF patients. Genotyping (ABCG2, ABCB1, CYP3A4*22, CYP3A5*3) was performed by TaqMan assays, and apixaban quantified by mass spectrometry. The typical patient was on average …

Off-Label Use Of Second Generation Antipsychotics In Primary Care -An Exploratory Study, Nima Gheisarzadeh

Electronic Thesis and Dissertation Repository

Over the past two decades, the use of antipsychotics has increased tremendously worldwide, and second-generation antipsychotics (SGAs) have been the main driver of this trend. The extensive use of SGAs for off-label purposes has raised concerns over their role in clinical practice. In particular, studies have revealed serious metabolic and cardiovascular effects, and evidence is lacking on SGAs’ effectiveness. Despite the concerns, the extent and pattern of SGAs’ off-label use is largely unknown within the context of the Canadian primary health care system. Using electronic medical record (EMR) data from 14 practices in southwestern Ontario, we investigated the number of …