Medicine and Health Sciences Commons^™

Intervention For Cognitive Reserve Enhancement In Delaying The Onset Of Alzheimer's Symptomatic Expression (Increase), A Randomized Controlled Trial: Rationale, Study Design, And Protocol, Daniela C. Moga, Brooke F. Beech, Erin L. Abner, Frederick A. Schmitt, Riham H. El Khouli, Ashley I. Martinez, Lynne Eckmann, Mark Huffmyer, Rosmy George, Gregory A. Jicha

Pharmacy Practice and Science Faculty Publications

BACKGROUND: The course of Alzheimer's disease (AD) includes a 10-20-year preclinical period with progressive accumulation of amyloid β (Aβ) plaques and neurofibrillary tangles in the absence of symptomatic cognitive or functional decline. The duration of this preclinical stage in part depends on the rate of pathologic progression, which is offset by compensatory mechanisms, referred to as cognitive reserve (CR). Comorbid medical conditions, psychosocial stressors, and inappropriate medication use may lower CR, hastening the onset of symptomatic AD. Here, we describe a randomized controlled trial (RCT) designed to test the efficacy of a medication therapy management (MTM) intervention to reduce inappropriate …

Systemic Toxicity Reported For Cdk8/19 Inhibitors Cct251921 And Msc2530818 Is Not Due To Target Inhibition, Mengqian Chen, Jing Li, Jiaxin Liang, Zanshé S. Thompson, Katie Kathrein, Eugenia Broude, Igor Roninson

Faculty Publications

CDK8/19 kinases, which mediate transcriptional reprogramming, have become an active target for cancer drug discovery. Several small-molecule CDK8/19 inhibitors showed in vivo efficacy and two have entered clinical trials, with no significant toxicities reported. However, Clarke et al. (eLife 2016; 5; e20722) found severe systemic toxicity associated with two potent CDK8/19 inhibitors, Cmpd3 (CCT251921) and Cmpd4 (MSC2530818), and suggested that their toxicity was due to on-target effects. Here, we compared five CDK8/19 inhibitors: Cmpd3, Cmpd4, Senexin B, 16-didehydro-cortistatin A (dCA) and 15w, in different assays. Only Cmpd4 showed striking toxicity in developing zebrafish. In cell-based assays for CDK8 and CDK19 …

Co-Prescription Network Reveals Social Dynamics Of Opioid Doctor Shopping, Brea L. Perry, Kai Cheng Yang, Patrick Kaminski, Meltem Odabas, Jaehyuk Park, Michelle M. Martel, Carrie B. Oser, Patricia R. Freeman, Yong-Yeol Ahn, Jeffery C. Talbert

Psychology Faculty Publications

This paper examines network prominence in a co-prescription network as an indicator of opioid doctor shopping (i.e., fraudulent solicitation of opioids from multiple prescribers). Using longitudinal data from a large commercially insured population, we construct a network where a tie between patients is weighted by the number of shared opioid prescribers. Given prior research suggesting that doctor shopping may be a social process, we hypothesize that active doctor shoppers will occupy central structural positions in this network. We show that network prominence, operationalized using PageRank, is associated with more opioid prescriptions, higher predicted risk for dangerous morphine dosage, opioid overdose, …

Multiple Sclerosis Outcomes After Cancer Immunotherapy, Catherine R. Garcia, Rani Jayswal, Val R. Adams, Lowell B. Anthony, John L. Villano

Markey Cancer Center Faculty Publications

INTRODUCTION: Neurological immune-related adverse events are a rare but potentially deadly complication after immune checkpoint inhibitor (ICI) treatment. As multiple sclerosis (MS) is an immune-mediated disease, it is unknown how ICI treatment may affect outcomes.

METHODS: We analyzed the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database for pembrolizumab, atezolizumab, nivolumab, ipilimumab, avelumab, and durvalumab 2 years prior their FDA approval until December 31, 2017, to include all cases with confirmed diagnosis/relapse of MS. We also included cases reported in the literature and a patient from our institution.

RESULTS: We identified 14 cases of MS …

Long-Term Safety And Efficacy Of Subcutaneous Pasireotide In Patients With Cushing's Disease: Interim Results From A Long-Term Real-World Evidence Study., Luca Manetti, Timo Deutschbein, Jochen Schopohl, Kevin C J Yuen, Michael Roughton, Ulrike Kriemler-Krahn, Libuse Tauchmanova, Ricardo Maamari, Carla Giordano

Articles, Abstracts, and Reports

PURPOSE: Clinical trials have demonstrated the favorable efficacy/safety profile of pasireotide in patients with Cushing's disease (CD). We report interim long-term results of an ongoing real-world evidence study of subcutaneous pasireotide in patients with CD.

METHODS: Adults with CD receiving pasireotide, initiated before (prior-use) or at study entry (new-use), were monitored for ≤ 3 years during a multicenter observational study ( http://clinicaltrials.gov identifier NCT02310269). Primary objective was to assess long-term safety of pasireotide alone or with other CD therapies.

RESULTS: At the time of this interim analysis, 127 patients had received pasireotide (new-use, n = 31; prior-use, n = 96). …

Evaluation Of Prescribing Patterns Of Long-Acting Injectable Antipsychotics Within A Community Health System., Jared Netley Pharmd, Mpa, Bcps, Jamie Gaul Pharmd, Bcps, Chelsea L Ferguson Pharmd

Parkview Pharmacy Department

PURPOSE/BACKGROUND: Long-acting injectable antipsychotics (LAIAs) are used in the management of schizophrenia, bipolar disorder, and related psychiatric conditions. The efficacy of LAIAs has been established in randomized controlled trials; however, usage of LAIAs outside of randomized controlled trials may not correlate to naturalistic prescribing habits. The purpose of this analysis was to evaluate the prescribing patterns of LAIAs within our health system and identify any inconsistencies between medications' published labeling information and clinical practice.

METHODS/PROCEDURES: All patients who received a LAIA at the time of the analysis were included for review. Areas of inconsistency between the prescribed LAIA and each …

Association Of Naloxone Coprescription Laws With Naloxone Prescription Dispensing In The United States, Minji Sohn, Jeffery C. Talbert, Zhengyan Huang, Michelle R. Lofwall, Patricia R. Freeman

Institute for Pharmaceutical Outcomes and Policy Faculty Publications

Importance: To mitigate the opioid overdose crisis, states have implemented a variety of legal interventions aimed at increasing access to the opioid antagonist naloxone. Recently, Virginia and Vermont mandated the coprescription of naloxone for potentially at-risk patients.

Objective: To assess the association between naloxone coprescription legal mandates and naloxone dispensing in retail pharmacies.

Design, Setting, and Participants: This was a population-based, state-level cohort study. The sample included all prescriptions dispensed for naloxone in the retail pharmacy setting contained in IQVIA's national prescription audit, which represents 90% of all retail pharmacies in the United States. The unit of observation was state-month …

Impact Of High Volume Energy Drink Consumption On Electrocardiographic And Blood Pressure Parameters: A Randomized Trial, Sachin A. Shah, Andy H. Szeto, Raechel Farewell, Allen Shek, Dorothy Fan, Kathy N. Quach, Mouchumi Bhattacharyya, Jasmine Elmiari, Winny Chan, Kate O'Dell, Nancy Nguyen, Tracey J. Mcgaughey, Javed M. Nasir, Sanjay Kaul

School of Pharmacy Faculty Articles

Background Energy drinks have been linked to an increase in emergency room visits and deaths. We aim to determine the impact of energy drinks on electrocardiographic and hemodynamic parameters in young healthy volunteers. Methods and Results A randomized, double-masked, placebo-controlled, crossover study was conducted in healthy volunteers. Participants consumed 32 oz of either energy drink A, energy drink B, or placebo within 60 minutes on 3 study days with a 6-day washout period in between. The primary end point of QT c interval and secondary end points of QT interval, PR interval, QRS duration, heart rate, and brachial and central …

A High-Throughput Screen Indicates Gemcitabine And Jak Inhibitors May Be Useful For Treating Pediatric Aml, Christina D. Drenberg, Anang Shelat, Jinjun Dang, Anitria Cotton, Shelley J. Orwick, Mengyu Li, Jae Yoon Jeon, Qiang Fu, Daelynn R. Buelow, Marissa Pioso, Shuiying Hu, Hiroto Inaba, Raul C. Ribeiro, Jeffrey E. Rubnitz, Tanja A. Gruber, R. Kiplin Guy, Sharyn D. Baker

Pharmaceutical Sciences Faculty Publications

Improvement in survival has been achieved for children and adolescents with AML but is largely attributed to enhanced supportive care as opposed to the development of better treatment regimens. High risk subtypes continue to have poor outcomes with event free survival rates < 40% despite the use of high intensity chemotherapy in combination with hematopoietic stem cell transplant. Here we combine high-throughput screening, intracellular accumulation assays, and in vivo efficacy studies to identify therapeutic strategies for pediatric AML. We report therapeutics not currently used to treat AML, gemcitabine and cabazitaxel, have broad anti-leukemic activity across subtypes and are more effective relative to the AML standard of care, cytarabine, both in vitro and in vivo. JAK inhibitors are selective for acute megakaryoblastic leukemia and significantly prolong survival in multiple preclinical models. Our approach provides advances in the development of treatment strategies for pediatric AML.

Comparative Effectiveness Of Drugs Used To Constrict The Patent Ductus Arteriosus: A Secondary Analysis Of The Pda-Tolerate Trial (Nct01958320)., Melissa Liebowitz, Joseph Kaempf, Omer Erdeve, Ali Bulbul, Stellan Håkansson, Johanna Lindqvist, Aijaz Farooqi, Anup Katheria, Jason Sauberan, Jaideep Singh, Kelly Nelson, Andrea Wickremasinghe, Lawrence Dong, Denise C Hassinger, Susan W Aucott, Madoka Hayashi, Anne Marie Heuchan, William A Carey, Matthew Derrick, Ilene Sue Wolf, Amy Kimball, Meera Sankar, Tina Leone, Jorge Perez, Arturo Serize, Ronald I Clyman

Articles, Abstracts, and Reports

OBJECTIVE: To evaluate the effectiveness of drugs used to constrict patent ductus arteriosus (PDA) in newborns < 28 weeks.

METHODS: We performed a secondary analysis of the multi-center PDA-TOLERATE trial (NCT01958320). Infants with moderate-to-large PDAs were randomized 1:1 at 8.1 ± 2.1 days to either Drug treatment (n = 104) or Conservative management (n = 98). Drug treatments were assigned by center rather than within center (acetaminophen: 5 centers, 27 infants; ibuprofen: 7 centers, 38 infants; indomethacin: 7 centers, 39 infants).

RESULTS: Indomethacin produced the greatest constriction (compared with spontaneous constriction during Conservative management): RR (95% CI) = 3.21 (2.05-5.01)), followed by ibuprofen …

A Randomized, Controlled Trial On The Effects Of Almonds On Lipoprotein Response To A Higher Carbohydrate, Lower Fat Diet In Men And Women With Abdominal Adiposity., Paul T. Williams, Nathalie Bergeron, Sally Chiu, Ronald M. Krauss

Faculty Publications & Research of the TUC College of Pharmacy

BACKGROUND: Almonds have been shown to lower LDL cholesterol but there is limited information regarding their effects on the dyslipidemia characterized by increased levels of very low density lipoproteins (VLDL) and small, dense low-density lipoprotein (LDL) particles that is associated with abdominal adiposity and high carbohydrate intake. The objective of the present study was to test whether substitution of almonds for other foods attenuates carbohydrate-induced increases in small, dense LDL in individuals with increased abdominal adiposity.

METHODS: This was a randomized cross-over study of three 3wk diets, separated by 2wk washouts: a higher-carbohydrate (CHO) reference diet (CHO

RESULTS: Relative to …

A Rational Approach For Creating Peptides Mimicking Antibody Binding, Sameer Sachdeva, Hyun Joo, Jerry Tsai, Bhaskara Jasti, Xiaoling Li

School of Pharmacy Faculty Articles

This study reports a novel method to design peptides that mimic antibody binding. Using the Knob-Socket model for protein-protein interaction, the interaction surface between Cetuximab and EGFR was mapped. EGFR binding peptides were designed based on geometry and the probability of the mapped knob-sockets pairs. Designed peptides were synthesized and then characterized for binding specificity, affinity, cytotoxicity of drug-peptide conjugate and inhibition of phosphorylation. In cell culture studies, designed peptides specifically bind and internalize to EGFR overexpressing cells with three to four-fold higher uptake compared to control cells that do not overexpress EGFR. The designed peptide, Pep11, bound to EGFR …

Biosynthetic And Synthetic Strategies For Assembling Capuramycin-Type Antituberculosis Antibiotics, Ashley L. Biecker, Xiaodong Liu, Jon S. Thorson, Zhaoyong Yang, Steven G. Van Lanen

Pharmaceutical Sciences Faculty Publications

Mycobacterium tuberculosis (Mtb) has recently surpassed HIV/AIDS as the leading cause of death by a single infectious agent. The standard therapeutic regimen against tuberculosis (TB) remains a long, expensive process involving a multidrug regimen, and the prominence of multidrug-resistant (MDR), extensively drug-resistant (XDR), and totally drug-resistant (TDR) strains continues to impede treatment success. An underexplored class of natural products—the capuramycin-type nucleoside antibiotics—have been shown to have potent anti-TB activity by inhibiting bacterial translocase I, a ubiquitous and essential enzyme that functions in peptidoglycan biosynthesis. The present review discusses current literature concerning the biosynthesis and chemical synthesis of capuramycin …

Developing A Biased Unmatched Bivalent Ligand (Bumbl) Design Strategy To Target The Gpcr Homodimer Allosteric Signaling (Camp Over Β-Arrestin 2 Recruitment) Within The Melanocortin Receptors., Cody J Lensing, Katie T Freeman, Sathya M Schnell, Robert Charles Speth, Adam T Zarth, Carrie Haskell-Luevano

Faculty Articles

Understanding the functional relevance of G protein-coupled receptor (GPCR) homodimerization has been limited by the insufficient tools to assess asymmetric signaling occurring within dimers comprised of the same receptor type. We present unmatched bivalent ligands (UmBLs) to study the asymmetric function of melanocortin homodimers. UmBLs contain one agonist and one antagonist pharmacophore designed to target a melanocortin homodimer such that one receptor is occupied by an agonist and the other receptor by an antagonist pharmacophore. First-in-class biased UmBLs (BUmBLs) targeting the human melanocortin-4 receptor (hMC4R) were discovered. The BUmBLs displayed biased agonism by potently stimulating cAMP signaling (EC

Hiv Viral Rebound Due To A Possible Drug-Drug Interaction Between Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide And Calcium-Containing Products: Report Of 2 Cases, S. Lena Kang-Birken, Dena El-Sayed, John Prichard

School of Pharmacy Faculty Articles

Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) is a potent fixed-dose, once-daily regimen for HIV-1 treatment and has rare emergence of drug resistance. We report a potential drug-drug interaction in 2 female patients both receiving treatment for HIV and cerebral toxoplasmosis: one case between E/C/F/TAF with calcium carbonate and a second case involving leucovorin as calcium salt. Both cases resulted in rise in HIV RNA levels and emergence of M184 V mutation and resistance to elvitegravir and raltegravir. To the best of our knowledge, these 2 cases are the first reports of rapid emergence of mutation from coadministration of E/C/F/TAF and calcium.

Responsible, Safe, And Effective Use Of Biologics In The Management Of Low Back Pain: American Society Of Interventional Pain Physicians (Asipp) Guidelines, Annu Navani, Laxmaiah Manchikanti, Sheri L. Albers, Richard E. Latchaw, Jaya Sanapati, Alan David Kaye, Sairam Atluri, Sheldon Jordan, Ashim Gupta, David Cedeno, Alejandro Vallejo, Bert Fellows, Nebojsa Nick Knezevic, Miguel Pappolla, Sudhir Diwan, Andrea M. Trescot, Amol Soin, Adam M. Kaye, Steve M. Aydin, Aaron K. Calodney, Kenneth D. Candido, Sanjay Bakshi, Ramsin M. Benyamin, Ricardo Vallejo, Art Watanabe, Douglas Beall, Todd P. Stitik, Patrick M. Foye, Erik M. Helander, Joshua A. Hirsch

School of Pharmacy Faculty Articles

BACKGROUND: Regenerative medicine is a medical subspecialty that seeks to recruit and enhance the body's own inherent healing armamentarium in the treatment of patient pathology. This therapy's intention is to assist in the repair, and to potentially replace or restore damaged tissue through the use of autologous or allogenic biologics. This field is rising like a Phoenix from the ashes of underperforming conventional therapy midst the hopes and high expectations of patients and medical personnel alike. But, because this is a relatively new area of medicine that has yet to substantiate its outcomes, care must be taken in its public …