Medical Pharmacology Commons^™

Buprenorphine In Neonatal Abstinence Syndrome., Walter K. Kraft

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Infants exposed in utero to opioids will demonstrate a withdrawal syndrome known as neonatal abstinence syndrome (NAS). Buprenorphine is a long-acting opioid with therapeutic use in medication-assisted treatment of opioid dependency in adults and adolescents. Emerging data from clinical trials and treatment cohorts demonstrate the efficacy and safety of sublingual buprenorphine for those infants with NAS who require pharmacologic treatment. Pharmacometric modeling will assist in defining the exposure-response relationships and facilitate dose optimization.

Neonatal Safety Information Reported To The Fda During Drug Development Studies., Debbie Avant, Gerri Baer, Jason N. Moore, Panli Zheng, Alfred Sorbello, Ron Ariagno, Lynne Yao, Gilbert J. Burckart, Jian Wang

Department of Pharmacology and Experimental Therapeutics Faculty Papers

BACKGROUND: Relatively few neonatal drug development studies have been conducted, but an increase is expected with the enactment of the Food and Drug Administration Safety and Innovation Act (FDASIA). Understanding the safety of drugs studied in neonates is complicated by the unique nature of the population and the level of illness. The objective of this study was to examine neonatal safety data submitted to the FDA in studies pursuant to the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) between 1998 and 2015.

METHODS: FDA databases were searched for BPCA and/or PREA studies that enrolled …

Microrna Cluster Mir199a/214 Are Differentially Expressed In Female And Male Rats Following Nicotine Self-Administration, Steven T. Pittenger, Victoria L. Schaal, Dalia Moore, Rahul S. Guda, Sneh Koul, Sowmya V. Yelamanchili, Rick A. Bevins, Gurudutt Pendyala

Journal Articles: Pharmacology & Experimental Neuroscience

Previous research has established sex differences associated with nicotine intake, however a significant gap in knowledge remains regarding the molecular mechanisms that govern these differences at the transcriptional level. One critical regulator of transcription are microRNAs (miRNAs). miRNAs are a family of non-coding RNAs that regulate an array of important biological functions altered in several disease states, including neuroadaptive changes within the brain associated with drug dependence. We examined the prefrontal cortex (PFC) from male and female Sprague-Dawley rats following self-administration (22 days) of nicotine or yoked saline controls using next generation RNA-Sequencing (RNA-Seq) technology and found an array of …

Effects Of Chemotherapy On Motivated Behavior And Opioid Reward In Rats, Luke P. Legakis

Theses and Dissertations

Paclitaxel, vincristine, oxaliplatin, and bortezomib are cancer chemotherapy drugs with adverse effects that include chemotherapy-induced neuropathic pain (CINP) as well as depression of behavior and mood. In the clinical setting, opioids are often used concurrently with or following chemotherapy to treat pain related to the cancer or CINP, but repeated opioid exposure can also increase the risk of opioid abuse. This dissertation evaluated the effect of chemotherapy treatment on motivated behaviors and opioid reward in rats. The main findings of this evaluation are as follows: (1) Chemotherapy, at doses that produce robust and sustained mechanical hypersensitivity produce only weak or …

Investigating The Role Of Nicotinic Acetylcholine Receptor Agonists In Lung Cancer Progression And Chemosensitivity In The Context Of Treating Chemotherapy-Induced Peripheral Neuropathy, Sarah L. Kyte

Theses and Dissertations

While cancer chemotherapy continues to significantly contribute to the number of cancer survivors, exposure to these drugs can often result in chemotherapy-induced peripheral neuropathy (CIPN), a consequence of peripheral nerve fiber dysfunction or degeneration. CIPN is characterized by sensory symptoms in the hands and feet, such as numbness, burning, and allodynia, resulting in an overall decrease in quality of life. Paclitaxel (Taxol), a microtubule poison that is commonly used to treat breast, lung, and ovarian cancers, has been found to cause CIPN in 59-78% of cancer patients. There is currently no effective preventative or therapeutic treatment for this side effect, …

Novel Insights Into The Contribution Of Cellular Senescence To Cancer Therapy: Reversibility, Dormancy And Senolysis., Tareq Saleh

Theses and Dissertations

Cellular senescence a specialized form of growth arrest that contributes to the pathogenesis of several aging-related disorders including cancer. While by definition tumor cells are considered immortalized, they can undergo senescence when exposed to conventional and targeted cancer therapy. Therapy-Induced Senescence (TIS) represents a fundamental response to therapy and impacts its outcomes. However, TIS has been considered a positive therapeutic goal since senescent tumor cells are expected to enter a state of permanent growth abrogation. In this work we examined the hypothesis that a subpopulation of senescent cells can re-acquire proliferative potential after a state of senescent dormancy, indicating that …

Gastrointestinal Microbiota Modulate Antinociceptive Tolerance Development In Mice With Chronic Morphine Exposure, Ryan A. Mischel

Theses and Dissertations

In October 2017, the United States government declared a state of public health emergency in response to the burgeoning prescription opioid epidemic. Opioid analgesics are the gold standard of therapy for moderate to severe pain, but their clinical utility is greatly limited by analgesic tolerance – a primary driver of diminished pain control and opioid dose escalations. Integral in this process are primary afferent sensory neurons in dorsal root ganglia (DRG), the first-order components of nociceptive sensation. With surmounting evidence that morphine and other narcotics can alter gut microbial composition and promote bacterial translocation to other tissues, a question arises …

Development And Validation Of A Semi-Physiological Pharmacokinetic (Pbpk) Model To Predict Systemic And Pulmonary Exposures After Intravenous, Oral Administration And Pulmonary Inhalation Of Selected Drugs, Budesonide, Tobramycin And Ciprofloxacin, In Humans, Bishoy Hanna

Theses and Dissertations

Using a semi-PBPK modeling/quantitative meta-analysis approach, this project investigated what factors affect pulmonary and systemic exposures of Budesonide (BUD), Tobramycin (TOB), and Ciprofloxacin (CIP) after inhalation:

Three structurally different pulmonary disposition models were developed for each drug, including pulmonary absorption (all three), excretion (TOB and CIP) and sequestration (TOB) in a peripheral and central lung compartment. Systemic disposition parameters were estimated using available human mean plasma (c_p(t)) and sputum (c_s(t)) concentration profiles after IV administration, and GI absorption parameters were estimated from these profiles after oral administration. Pulmonary disposition parameters were estimated from c_p(t) …

Examination Of Venous Thromboembolism Prophylaxis In Patients Undergoing Total Knee Arthroplasty, William Kucera

Physician Assistant Scholarly Project Papers

Elective total knee arthroplasty (TKA) is the most frequently performed inpatient surgical procedure in the United States (Kurtz, Ong, Lau, Mowat, & Halpern 2007). Complications of this procedure include deep vein thrombosis (DVT) and pulmonary embolism (PE), collectively referred to as venous thromboembolism (VTE). Various pharmacological agents exist for VTE prophylaxis. Warfarin and low-molecular-weight heparin (LMWH) were commonly used for VTE prophylaxis in the past, but with the emergence of novel anticoagulants including factor Xa inhibitors and direct thrombin inhibitors (DTIs), warfarin is used far less frequently. Aspirin is also approved for VTE prophylaxis. The purpose of this study was …

United States State-Level Variation In The Use Of Neuraxial Analgesia During Labor For Pregnant Women, Alexander Butwick, Jason Bentley, Cynthia Wong, Jonathan Snowden, Eric Sun, Nan Guo

OHSU-PSU School of Public Health Faculty Publications and Presentations

Importance Neuraxial labor analgesia is recognized as the most effective method of providing pain relief during labor. Little is known about variation in the rates of neuraxial analgesia across US states. Identifying the presence and extent of variation may provide insights into practice variation and may indicate where access to neuraxial analgesia is inadequate. Objective To test the hypothesis that variation exists in neuraxial labor analgesia use among US states. Design, Setting, and Participants Retrospective, population …

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 …