Medical Pharmacology Commons^™

Translating Genetic And Preclinical Findings Into Autism Therapies, Maria Chahrour, Robin Kleiman, M Chiara Manzini

Pharmacology and Physiology Faculty Publications

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by social deficits and repetitive/restrictive interests. ASD is associated with multiple comorbidities, including intellectual disability, anxiety, and epilepsy. Evidence that ASD is highly heritable has spurred major efforts to unravel its genetics, revealing possible contributions from hundreds of genes through rare and common variation and through copy-number changes. In this perspective, we provide an overview of the current state of ASD genetics and of how genetic research has spurred the development of in vivo and in vitro models using animals and patient cells to evaluate the impact of genetic mutations …

Subanesthetic Ketamine For Postoperative Analgesia: An Evidenced-Based Project, Jeremy Vance

Doctoral Projects

Roughly 100 million surgical procedures are performed in the United States (U.S.) each year and more than 80% of these patients experience acute postoperative pain. Pain costs the U.S. an estimated $560 to $635 billion annually and is a significant contributor to national rates of mortality, morbidity, and disability. Despite these findings, patients continue to receive suboptimal postoperative pain relief.

The adjunct administration of subanesthetic ketamine is opioid-sparing and can improve the effectiveness of a multimodal pain management approach. This project used an exploratory descriptive design to examine how an evidence-based presentation impacted the clinical practice of certified registered nurse …

Hydroxyurea Differentially Modulates Activator And Repressors Of Γ-Globin Gene In Erythroblasts Of Responsive And Non-Responsive Patients With Sickle Cell Disease In Correlation With Index Of Hydroxyurea Responsiveness, Xingguo Zhu, Tianxiang Hu, Meng Hsuan Ho, Yongchao Wang, Miao Yu, Niren Patel, Wenhu Pi, Jeong-Hyeon Choi, Hongyan Xu, Vadivel Ganapathy, Ferdane Kutlar, Abdullah Kutlar, Dorothy Tuan

Pharmacology and Nutritional Sciences Faculty Publications

Hydroxyurea (HU), the first of two drugs approved by the US Food and Drug Administration for treating patients with sickle cell disease (SCD), produces anti-sickling effect by re-activating fetal γ-globin gene to enhance production of fetal hemoglobin. However, approximately 30% of the patients do not respond to HU therapy. The molecular basis of non-responsiveness to HU is not clearly understood. To address this question, we examined HU-induced changes in the RNA and protein levels of transcription factors NF-Y, GATA-1, -2, BCL11A, TR4, MYB and NF-E4 that assemble the γ-globin promoter complex and regulate transcription of γ-globin gene. In erythroblasts cultured …

Comparative Effectiveness And Safety Of Empagliflozin On Cardiovascular Mortality And Morbidity In Adults With Type 2 Diabetes, Wilbert S. Aronow, Tatyana Shamliyan

NYMC Faculty Publications

Background: Based on a single placebo-controlled randomized clinical trial, empagliflozin is licensed to reduce cardiovascular death in diabetes and comorbid cardiovascular disease. Methods: We examined the comparative effectiveness of empagliflozin on mortality and cardiovascular morbidity in type 2 diabetes. We conducted random-effects direct frequentist meta-analyses of aggregate data and appraised the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Our search in PubMed, EMBASE, the Cochrane Library, clinicaltrials.gov, and PharmaPendium up to May 2017 identified 11 meta-analyses, multiple publications, and unpublished data from 29 randomized controlled trials (RCTs). Results: Empagliflozin reduces all-cause mortality [relative …

Alcohol And Cancer Stem Cells, Mei Xu, Jia Luo

Pharmacology and Nutritional Sciences Faculty Publications

Heavy alcohol consumption has been associated with increased risk of several cancers, including cancer of the colon, rectum, female breast, oral cavity, pharynx, larynx, liver, and esophagus. It appears that alcohol exposure not only promotes carcinogenesis but also enhances the progression and aggressiveness of existing cancers. The molecular mechanisms underlying alcohol tumor promotion, however, remain unclear. Cancer stem cells (CSC), a subpopulation of cancer cells with self-renewal and differentiation capacity, play an important role in tumor initiation, progression, metastasis, recurrence, and therapy resistance. The recent research evidence suggests that alcohol increases the CSC population in cancers, which may underlie alcohol-induced …

Natural Bioactive Compounds: Alternative Approach To The Treatment Of Glioblastoma Multiforme, Vilas Desai, Alok Bhushan

College of Pharmacy Faculty Papers

Glioblastoma multiforme (GBM) is the most frequent, primary malignant brain tumor prevalent in humans. GBM characteristically exhibits aggressive cell proliferation and rapid invasion of normal brain tissue resulting in poor patient prognosis. The current standard of care of surgical resection followed by radiotherapy and chemotherapy with temozolomide is not very effective. The inefficacy of the chemotherapeutic agents may be attributed to the challenges in drug delivery to the tumor. Several epidemiological studies have demonstrated the chemopreventive role of natural, dietary compounds in the development and progression of cancer. Many of these studies have reported the potential of using natural compounds …

Gucy2c Maintains Intestinal Lgr5+ Stem Cells By Opposing Er Stress, Crystal Kraft, Jeff A. Rappaport, Adam E. Snook, Amanda M. Pattison, John P. Lynch, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Long-lived multipotent stem cells (ISCs) at the base of intestinal crypts adjust their phenotypes to accommodate normal maintenance and post-injury regeneration of the epithelium. Their long life, lineage plasticity, and proliferative potential underlie the necessity for tight homeostatic regulation of the ISC compartment. In that context, the guanylate cyclase C (GUCY2C) receptor and its paracrine ligands regulate intestinal epithelial homeostasis, including proliferation, lineage commitment, and DNA damage repair. However, a role for this axis in maintaining ISCs remains unknown. Transgenic mice enabling analysis of ISCs (Lgr5-GFP) in the context of GUCY2C elimination (Gucy2c^-/-) were combined with immunodetection techniques …

Epigenetic Impact Of Endocrine Disrupting Chemicals On Lipid Homeostasis And Atherosclerosis: A Pregnane X Receptor-Centric View, Robert N. Helsley, Changcheng Zhou

Pharmacology and Nutritional Sciences Faculty Publications

Despite the major advances in developing diagnostic techniques and effective treatments, atherosclerotic cardiovascular disease (CVD) is still the leading cause of mortality and morbidity worldwide. While considerable progress has been achieved to identify gene variations and environmental factors that contribute to CVD, much less is known about the role of “gene–environment interactions” in predisposing individuals to CVD. Our chemical environment has significantly changed in the last few decades, and there are more than 100,000 synthetic chemicals in the market. Recent large-scale human population studies have associated exposure to certain chemicals including many endocrine disrupting chemicals (EDCs) with increased CVD risk, …

Deletion Of The Nr4a Nuclear Receptor Nor1 In Hematopoietic Stem Cells Reduces Inflammation But Not Abdominal Aortic Aneurysm Formation, Hua Qing, Karrie L. Jones, Elizabeth B. Heywood, Hong Lu, Alan Daugherty, Dennis Bruemmer

Pharmacology and Nutritional Sciences Faculty Publications

Background: The NR4A3 orphan nuclear hormone receptor, NOR1, functions as a constitutively active transcription factor to regulate inflammation, proliferation, and cell survival during pathological vascular remodeling. Inflammatory processes represent key mechanisms leading to abdominal aortic aneurysm (AAA) formation. However, a role of NOR1 in AAA formation has not been investigated previously.

Methods: Inflammatory gene expression was analyzed in bone marrow-derived macrophages isolated from NOR1-deficient mice. Low-density lipoprotein receptor-deficient (LDLr^−/−) mice were irradiated and reconstituted with hematopoietic stem cells obtained from NOR1−/− or wild-type littermate mice. Animals were infused with angiotensin II and fed a diet enriched in saturated …

Finasteride As A Model For Personalized Medicine, Ion G. Motofei, David L. Rowland, Ioana Păunică, Octavian C. Tănăsescu, Petrişor Banu, Stana Păunică

Journal of Mind and Medical Sciences

The side effects of Finasteride are currently a subject of controversy. Some studies report minor or acceptable adverse effects, which decrease after a variable period of time so that they do not necessitate terminating Finasteride administration. However, several clinical and neuro-endocrine studies show that some adverse effects persist indefinitely in the form of post-Finasteride syndrome, even after the drug cessation. This paper presents a possible explanation for these inconsistent findings. First, the study design of either informing or not informing patients prior therapy about possible adverse effects can influence the incidence and magnitude of reported adverse effects. Second, structural and …

An Ethnobotanical Examination Of Traditional Medicine In Ngezi Forest Reserve, Tyler Tsang

Independent Study Project (ISP) Collection

Traditional medicine is an important aspect of the both the culture and health of communities worldwide. Ngezi Forest Reserve is a protected area on Pemba Island which is part of the Zanzibar Archipelago. This forest contains a wealth of botanical diversity which includes many species of medicinal plants. Traditional healers (waganga) use these medicinal plants to heal members of the community. Interviews and forest walks with these healers were supplemented by consultations with a botanist to determine medicinal value of the forest and the surrounding areas. In compiling information from 15 healers in the area, 98 species of medicinal plants …

Medication Complications In Extracorporeal Membrane Oxygenation., Ami G. Shah, Michelle Peahota, Brandi Thoma, Walter K. Kraft

College of Pharmacy Faculty Papers

The need for extracorporeal membrane oxygenation (ECMO) therapy is a marker of disease severity for which multiple medications are required. The therapy causes physiologic changes that impact drug pharmacokinetics. These changes can lead to exposure-driven decreases in efficacy or increased incidence of side effects. The pharmacokinetic changes are drug specific and largely undefined for most drugs. We review available drug dosing data and provide guidance for use in the ECMO patient population.

Evaluating The Therapeutic Effect Of Purslane Extract On The Submandibular Salivary Glands Of Cyclosporine-A Treated Rats, Heba Mahmoud, Rabab T. Mubarak, Iman M. Aboushady

Dentistry

Salivary glands are affected by immunosuppressive drugs, like Cyclosporine-A (CsA) which plays a major role in transplant medicine. Thus, this work aimed to study the possible therapeutic effect of purslane on CsA induced salivary gland alterations.

Materials & Methods: 30 adult male albino rats were equally divided into 3 groups: control group ] received a vehicle, CsA group received 20 mg/kg/day of CsA, and combination group received CsA and 400mg/kg/day of purslane. Three weeks later rats were sacrified then the submandibular salivary glands were prepared for histological andKi67 immunohistochemical analysis, then the studied groups were statistically evaluated.

Results: Histological examination …

Structural Basis For Selective Inhibition Of Cyclooxygenase-1 (Cox-1) By Diarylisoxazoles Mofezolac And 3-(5-Chlorofuran-2-Yl)-5-Methyl-4-Phenylisoxazole (P6)., Gino Cingolani, Andrea Panella, Maria Grazia Perrone, Paola Vitale, Giuseppe Di Mauro, Cosimo G G. Fortuna, Roger S. Armen, Savina Ferorelli, William L. Smith, Antonio Scilimati

Department of Biochemistry and Molecular Biology Faculty Papers

The diarylisoxazole molecular scaffold is found in several NSAIDs, especially those with high selectivity for COX-1. Here, we have determined the structural basis for COX-1 binding to two diarylisoxazoles: mofezolac, which is polar and ionizable, and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6) that has very low polarity. X-ray analysis of the crystal structures of COX-1 bound to mofezolac and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole allowed the identification of specific binding determinants within the enzyme active site, relevant to generate structure/activity relationships for diarylisoxazole NSAIDs.

The Heat-Stable Enterotoxin Receptor, Guanylyl Cyclase C, As A Pharmacological Target In Colorectal Cancer Immunotherapy: A Bench-To-Bedside Current Report., Trevor R. Baybutt, Allison A. Aka, Adam E. Snook

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Cancer immunotherapy is becoming a routine treatment modality in the oncology clinic, in spite of the fact that it is a relatively nascent field. The challenge in developing effective immunotherapeutics is the identification of target molecules that promote anti-tumor efficacy across the patient population while sparing healthy tissue from damaging autoimmunity. The intestinally restricted receptor guanylyl cyclase C (GUCY2C) is a target that has been investigated for the treatment of colorectal cancer and numerous animal, and clinical studies have demonstrated both efficacy and safety. Here, we describe the current state of GUCY2C-directed cancer immunotherapy and the future directions of this …

Gucy2c Signaling Opposes The Acute Radiation-Induced Gi Syndrome., Peng Li, Evan Wuthrick, Jeff A. Rappaport, Crystal Kraft, Jieru E. Lin, Glen Marszalowicz, Adam E. Snook, Tingting Zhan, Terry M. Hyslop, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

High doses of ionizing radiation induce acute damage to epithelial cells of the gastrointestinal (GI) tract, mediating toxicities restricting the therapeutic efficacy of radiation in cancer and morbidity and mortality in nuclear disasters. No approved prophylaxis or therapy exists for these toxicities, in part reflecting an incomplete understanding of mechanisms contributing to the acute radiation-induced GI syndrome (RIGS). Guanylate cyclase C (GUCY2C) and its hormones guanylin and uroguanylin have recently emerged as one paracrine axis defending intestinal mucosal integrity against mutational, chemical, and inflammatory injury. Here, we reveal a role for the GUCY2C paracrine axis in compensatory mechanisms opposing RIGS. …

Hydroxyurea Lowers The Frequency Of Sickle Cell Vaso-Occlusive Crises, Corey S. Macrander

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med 1995;(332):1317-1322 doi: 10.1056/nejm199505183322001

Temporal Changes In Cortical And Hippocampal Expression Of Genes Important For Brain Glucose Metabolism Following Controlled Cortical Impact Injury In Mice, June Zhou, Mark Burns, Linda Huynh, Sonia Villapol, Daniel D. Taub, Juan M. Saavedra, Marc R. Blackman

Pharmacology and Physiology Faculty Publications

Traumatic brain injury (TBI) causes transient increases and subsequent decreases in brain glucose utilization. The underlying molecular pathways are orchestrated processes and poorly understood. In the current study, we determined temporal changes in cortical and hippocampal expression of genes important for brain glucose/lactate metabolism and the effect of a known neuroprotective drug telmisartan on the expression of these genes after experimental TBI. Adult male C57BL/6J mice (n = 6/group) underwent sham or unilateral controlled cortical impact (CCI) injury. Their ipsilateral and contralateral cortex and hippocampus were collected 6 h, 1, 3, 7, 14, 21, and 28 days after injury. …

Peer Review Certifies Quality And Innovation In Clinical Pharmacology & Therapeutics., Scott A. Waldman, Andre M. Terzic

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Clinical Pharmacology & Therapeutics (CPT) is an established voice of the discipline, a trusted source of new knowledge showcasing discovery, translation, and application of novel therapeutic paradigms to advance the management of patients and populations. Identifying, evaluating, prioritizing, and disseminating the best science along the discovery-development-regulatory-utilization continuum are responsibilities shared through peer review. To enhance the uniformity of this essential component of quality assurance and innovation, and maximize the value of the journal and its contents to authors, reviewers, and the readership, we review key concepts concerning peer review as it specifically relates to CPT.

Drug-Induced Causes Of Secondary Hypertension, Wilbert S. Aronow

NYMC Faculty Publications

No abstract provided.

Aligning Opioid Prescribing Pathways, Andrea Lai, Outpatient Pharmacy, Haley Pelletier, Suneela Nayak, Stephen Tyzik, Ruth Hanselman

MaineHealth Maine Medical Center

There is a drug epidemic sweeping the State of Maine and it continues to worsen each passing year. In 2017, the Maine legislature passed Public Law Chapter 488 to strengthen the controlled substance prescription monitoring program. An outpatient pharmacy, located in a large acute care hospital, created a performance improvement project to clarify opioid prescription and resolve any non-compliance with Chapter 488.

After a root cause analysis, several KPIs were established to include tracking the number of phone calls made by pharmacists to non-compliant providers to clarify scripts, provide one on one education and ultimately resolve non-compliance. Repeat offenders were …

Patient Fall Prevention, R9 West Cardiovascular, Cathy Palleschi, Suneela Nayak, Ruth Hanselman, Stephen Tyzik

MaineHealth Maine Medical Center

PATIENT FALL PREVENTION STRATEGIES IN AN ACUTE HOSPITAL

Every year in the United States, hundreds of thousands of patients fall resulting in injury. Injured patients often require prolonged hospital stays and a resultant increase in medical costs.

The purpose of this study was to identify the current state of fall prevention strategies on a hospital inpatient acute care cardiac unit. Through a root cause analysis, some deficiencies were identified and a process improvement plan was implemented.

Several positive outcomes were attained as a result of the countermeasures initiated. Patient falls per month and total waste in dollars saw a decline …

Communication Of Medication Side Effects In An Acute Care Hospital, Deb Bachand, Rachel Caiola, R6 Neurology Med-Surg Unit, Haley Pelletier, Brendan Lilley, Suneela Nayak, Ruth Hanselman, Stephen Tyzik

MaineHealth Maine Medical Center

COMMUNICATION OF MEDICATION SIDE EFFECTS IN AN ACUTE CARE HOSPITAL

Effective patient education of prescribed medication side effects improves patient safety and reduces overall risk. On an acute care hospital unit, nursing staff felt previous attempts at this education had been ineffective as demonstrated by their HCAHPs scores for communication about medications.

A root cause analysis demonstrated some flaws and several countermeasures were instituted. The goal of this KPI project was to attain a higher than national average for the specific HCAHPs score.

Post KPI inception, the unit’s HCAHPs data showed steady improvement. Within one month, the goal of an …

Overexpressed Somatic Alleles Are Enriched In Functional Elements In Breast Cancer., Paula Restrepo, Mercedeh Movassagh, Nawaf Alomran, Christian Miller, Muzi Li, Chris Trenkov, Yulian Manchev, Sonali Bahl, Stephanie Warnken, Liam Spurr, Tatiyana Apanasovich, Keith Crandall, Nathan Edwards, Anelia Horvath

Pharmacology and Physiology Faculty Publications

Asymmetric allele content in the transcriptome can be indicative of functional and selective features of the underlying genetic variants. Yet, imbalanced alleles, especially from diploid genome regions, are poorly explored in cancer. Here we systematically quantify and integrate the variant allele fraction from corresponding RNA and DNA sequence data from patients with breast cancer acquired through The Cancer Genome Atlas (TCGA). We test for correlation between allele prevalence and functionality in known cancer-implicated genes from the Cancer Gene Census (CGC). We document significant allele-preferential expression of functional variants in CGC genes and across the entire dataset. Notably, we find frequent …

Ag-205 For The Treatment Of Breast Cancer, Rolf Joseph Craven

Pharmacology and Nutritional Sciences Faculty Patents

Compositions, methods, and combination therapies for the treatment of cancers, including lymphomas, leukemias, melanomas, lung cancer, and metastatic disease, are provided. Specifically, compositions comprising ligands to Pgrmc1 are disclosed for use in treating and inhibiting tumor growth and progression and inhibition of metastases. The compositions and methods using these ligands can be used alone or in combination with other reagents and cancer treatment modalities.

Pathologic Evaluation Of Tumor-Associated Macrophage Density And Vessel Inflammation In Invasive Breast Carcinomas, Yoshihiro Morita, Roy Zhang, Macall Leslie, Smita Adhikari, Nafis Hasan, Inna Chervoneva, Hallgeir Rui, Takemi Tanaka

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Tumor-associated macrophages (TAMs) are major constituents of the tumor microenvironment in solid tumors and have been implicated as mediators of tumor progression, invasion and metastasis. Correspondingly, accumulation of TAMs is associated with unfavorable clinical outcomes in numerous types of solid tumors. E-selectin is a hallmark of inflammation and a key adhesion molecule that accommodates the initial contact of circulating immune cells with the inflamed vessel surface. Currently, the association between E-selectin and TAMs is not fully elucidated; therefore, the present study investigated the association between vessel inflammation, TAM infiltration, and clinical outcome in breast cancer. A total of 53 procedure-naïve …

Brain Microvascular Injury And White Matter Disease Provoked By Diabetes-Associated Hyperamylinemia, Han Ly, Nirmal Verma, Fengen Wu, Miao Liu, Kathryn E. Saatman, Peter T. Nelson, John T. Slevin, Larry B. Goldstein, Geert Jan Biessels, Florin Despa

Pharmacology and Nutritional Sciences Faculty Publications

OBJECTIVE: The brain blood vessels of patients with type 2 diabetes and dementia have deposition of amylin, an amyloidogenic hormone cosecreted with insulin. It is not known whether vascular amylin deposition is a consequence or a trigger of vascular injury. We tested the hypothesis that the vascular amylin deposits cause endothelial dysfunction and microvascular injury and are modulated by amylin transport in the brain via plasma apolipoproteins.

METHODS: Rats overexpressing amyloidogenic (human) amylin in the pancreas (HIP rats) and amylin knockout (AKO) rats intravenously infused with aggregated amylin were used for in vivo phenotyping. We also carried out biochemical analyses …

The Role Of Hif-1Α In Intestinal Epithelial Barrier Function In Alcoholic Liver Disease., Tuo Shao

Electronic Theses and Dissertations

Hypoxia inducible factor 1 α (HIF1α) is an oxygen-responsive subunit. HIF-1α plays a pivotal role in many pathophysiological processes. In addition to oxygen availability, HIF-1α can be regulated by multiple other factors in response to various pathophysiological processes. Previous studies showed that hepatic HIF-1α could be beneficial or harmful in experimental alcoholic liver disease (ALD). However, the role of intestinal HIF-1α in ALD has not yet been studied. Given the critical role of the gut-liver axis in ALD, it is important to elucidate the role of intestinal epithelial HIF-1α in ALD. In the first chapter, we used wide type (WT) …

Induction Of Mir-155 After Brain Injury Promotes Type 1 Interferon And Has A Neuroprotective Effect., Emily Harrison, Kathleen M. Emanuel, Benjamin G. Lamberty, Brenda M. Morsey, Min Li, Matthew L. Kelso, Sowmya V. Yelamanchili, Howard S. Fox

Journal Articles: Pharmacology & Experimental Neuroscience

Traumatic brain injury (TBI) produces profound and lasting neuroinflammation that has both beneficial and detrimental effects. Recent evidence has implicated microRNAs (miRNAs) in the regulation of inflammation both in the periphery and the CNS. We examined the expression of inflammation associated miRNAs in the context of TBI using a mouse controlled cortical impact (CCI) model and found increased levels of miR-21, miR-223 and miR-155 in the hippocampus after CCI. The expression of miR-155 was elevated 9-fold after CCI, an increase confirmed by in situ hybridization (ISH). Interestingly, expression of miR-155 was largely found in neuronal nuclei as evidenced by co-localization …

Examining The Influence And Role Of Pharmacogenetics Among Children With Autism Spectrum Disorder, Nuha Shaker

Masters Theses & Specialist Projects

Pharmacogenetics is the study of genomic-guided individualized drug prescription that plays an important role in preventing the severe adverse effects of drugs, decreasing the time and cost of therapeutic choices, and directing healthcare professionals to choose medications that are effective and safe. It is noteworthy that this approach becomes highly beneficial in patients suffering from chronic diseases or disorders, since these conditions may require multiple and long term pharmacological therapies, as in children with autism spectrum disorder (ASD). However, public acceptance is a major challenge when implementation of pharmacogenetics merges into clinical practice. The purpose of this study is a) …