Medicine and Health Sciences Commons^™

The Concise Guide To Pharmacology 2023/24: Catalytic Receptors, Stephen P.H. Alexander, Doriano Fabbro, Eamonn Kelly, Alistair A. Mathie, John A. Peters, Emma L. Veale, Jane F. Armstrong, Elena Faccenda, Simon D. Harding, Jamie A. Davies, Annie Beuve, Peter Brouckaert, Clare Bryant, John C. Burnett, Richard W. Farndale, Andreas Friebe, John Garthwaite, Adrian J. Hobbs, Gavin E. Jarvis, Doris Koesling, Michaela Kuhn, David Macewan, Tom P. Monie, Lincoln R. Potter, Michael Russwurm, Harald H.H.W. Schmidt, Johannes-Peter Stasch, Scott A. Waldman

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and nearly 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org/), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It …

The Pharmacological Deprescription In Elderly Patients, Chelsey Ali, Daniel Huang, Charlene Tugwete, Stefano Del Canale, Vittorio Maio

College of Population Health Faculty Papers

No abstract provided.

Identification Of A Β-Arrestin-Biased Negative Allosteric Modulator For The Β2-Adrenergic Receptor, Michael Ippolito, Francesco De Pascali, Nathan Hopfinger, Konstantin E. Komolov, Daniela Laurinavichyute, Poli Adi Narayana Reddy, Leon A. Sakkal, Kyle Z. Rajkowski, Ajay P. Nayak, Justin Lee, Jordan Lee, Gaoyuan Cao, Preston S. Donover, Melvin Reichman, Stevens. An, Joseph M. Salvino, Raymond B. Penn, Roger S S. Armen, Charles P. Scott, Jeffrey L. Benovic

Department of Biochemistry and Molecular Biology Faculty Papers

Catecholamine-stimulated β2-adrenergic receptor (β2AR) signaling via the canonical Gs–adenylyl cyclase–cAMP–PKA pathway regulates numerous physiological functions, including the therapeutic effects of exogenous β-agonists in the treatment of airway disease. β2AR signaling is tightly regulated by GRKs and β-arrestins, which together promote β2AR desensitization and internalization as well as downstream signaling, often antithetical to the canonical pathway. Thus, the ability to bias β2AR signaling toward the Gs pathway while avoiding β-arrestin-mediated effects may provide a strategy to improve the functional consequences of β2AR activation. Since attempts to develop Gs-biased agonists and allosteric modulators for the β2AR have been largely unsuccessful, here we …

Intestinal Neuropod Cell Gucy2c Regulates Visceral Pain, Joshua R. Barton, Annie K. Londregran, Tyler D. Alexander, Ariana A. Entezari, Shely Bar-Ad, Lan Cheng, Angelo C. Lepore, Adam E. Snook, Manuel Covarrubias, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Visceral pain (VP) is a global problem with complex etiologies and limited therapeutic options. Guanylyl cyclase C (GUCY2C), an intestinal receptor producing cyclic GMP(cGMP), which regulates luminal fluid secretion, has emerged as a therapeutic target for VP. Indeed, FDA-approved GUCY2C agonists ameliorate VP in patients with chronic constipation syndromes, although analgesic mechanisms remain obscure. Here, we revealed that intestinal GUCY2C was selectively enriched in neuropod cells, a type of enteroendocrine cell that synapses with submucosal neurons in mice and humans. GUCY2Chi neuropod cells associated with cocultured dorsal root ganglia neurons and induced hyperexcitability, reducing the rheobase and increasing the resulting …

The Nogo Receptor Ngr2, A Novel Αvβ3 Integrin Effector, Induces Neuroendocrine Differentiation In Prostate Cancer, Fabio Quaglia, Shiv Ram Krishn, Khalid Sossey-Alaoui, Priyanka Shailendra Rana, Elzbieta Pluskota, Pyung Hun Park, Christopher D. Shields, Stephen Lin, Peter Mccue, Andrew V. Kossenkov, Yanqing Wang, David W. Goodrich, Sheng-Yu Ku, Himisha Beltran, William K. Kelly, Eva Corey, Maja Klose, Christine Bandtlow, Qin Liu, Dario C. Altieri, Edward F. Plow, Lucia R. Languino

Department of Cancer Biology Faculty Papers

Androgen deprivation therapies aimed to target prostate cancer (PrCa) are only partially successful given the occurrence of neuroendocrine PrCa (NEPrCa), a highly aggressive and highly metastatic form of PrCa, for which there is no effective therapeutic approach. Our group has demonstrated that while absent in prostate adenocarcinoma, the αVβ3 integrin expression is increased during PrCa progression toward NEPrCa. Here, we show a novel pathway activated by αVβ3 that promotes NE differentiation (NED). This novel pathway requires the expression of a GPI-linked surface molecule, NgR2, also known as Nogo-66 receptor homolog 1. We show here that NgR2 is upregulated by αVβ3, …

Ctpathway: A Crosstalk-Based Pathway Enrichment Analysis Method For Cancer Research, Haizhou Liu, Mengqin Yuan, Ramkrishna Mitra, Xu Zhou, Min Long, Wanyue Lei, Shunheng Zhou, Yu-E Huang, Fei Hou, Christine M. Eischen, Wei Jiang

Department of Cancer Biology Faculty Papers

Background: Pathway enrichment analysis (PEA) is a common method for exploring functions of hundreds of genes and identifying disease-risk pathways. Moreover, different pathways exert their functions through crosstalk. However, existing PEA methods do not sufficiently integrate essential pathway features, including pathway crosstalk, molecular interactions, and network topologies, resulting in many risk pathways that remain uninvestigated.

Methods: To overcome these limitations, we develop a new crosstalk-based PEA method, CTpathway, based on a global pathway crosstalk map (GPCM) with >440,000 edges by combing pathways from eight resources, transcription factor-gene regulations, and large-scale protein-protein interactions. Integrating gene differential expression and crosstalk effects in …

Lysine Methyltransferase Nsd1 And Cancers: Any Role In Melanoma?, Imène Krossa, Thomas Strub, Andrew E Aplin, Robert Ballotti, Corine Bertolotto

Department of Cancer Biology Faculty Papers

Epigenetic regulations, that comprise histone modifications and DNA methylation, are essential to processes as diverse as development and cancer. Among the histone post-translational modifications, lysine methylation represents one of the most important dynamic marks. Here, we focused on methyltransferases of the nuclear binding SET domain 1 (NSD) family, that catalyze the mono- and di-methylation of histone H3 lysine 36. We review the loss of function mutations of NSD1 in humans that are the main cause of SOTOS syndrome, a disease associated with an increased risk of developing cancer. We then report the role of NSD1 in triggering tumor suppressive or …

Steap1-4 (Six-Transmembrane Epithelial Antigen Of The Prostate 1-4) And Their Clinical Implications For Prostate Cancer, Michael Xu, Latese Evans, Candice L Bizzaro, Fabio Quaglia, Cecilia E Verrillo, Li Li, Julia Stieglmaier, M J Schiewer, Lucia R Languino, William Kevin Kelly

Department of Urology Faculty Papers

Six-Transmembrane Epithelial Antigen of the Prostate 1-4 (STEAP1-4) compose a family of metalloproteinases involved in iron and copper homeostasis and other cellular processes. Thus far, five homologs are known: STEAP1, STEAP1B, STEAP2, STEAP3, and STEAP4. In prostate cancer, STEAP1, STEAP2, and STEAP4 are overexpressed, while STEAP3 expression is downregulated. Although the metalloreductase activities of STEAP1-4 are well documented, their other biological functions are not. Furthermore, the properties and expression levels of STEAP heterotrimers, homotrimers, heterodimers, and homodimers are not well understood. Nevertheless, studies over the last few decades have provided sufficient impetus to investigate STEAP1-4 as potential biomarkers and therapeutic …

Ondansetron To Reduce Neonatal Opioid Withdrawal Severity: A Randomized Clinical Trial, Gary Peltz, Lauren M. Jansson, Susan Adeniyi-Jones, Carol Cohane, David Drover, Steven Shafer, Meiyue Wang, Manhong Wu, Balaji Govindaswami, Priya Jegatheesan, Cynthia Argani, Salwa Kahn, Walter K. Kraft

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Objective
To determine if treatment with a 5-HT3 antagonist (ondansetron) reduces need for opioid therapy in infants at risk for neonatal opioid withdrawal syndrome (NOWS).

Study Design
A multicenter, randomized, placebo controlled, double blind clinical trial of ninety (90) infants. The intervention arms were intravenous ondansetron or placebo during labor followed by a daily dose of ondansetron or placebo in infants for five days.

Results
Twenty-two (49%) ondansetron-treated and 26 (63%) placebo-treated infants required pharmacologic treatment (p>0.05). The Finnegan score was lower in the ondansetron-treated group (4.6 vs. 5.6, p=0.02). A non-significant trend was noted for the duration of …

A Telehealth-Delivered Tai Chi Intervention (Taichi4joint) For Managing Aromatase Inhibitor-Induced Arthralgia In Patients With Breast Cancer During Covid-19: Longitudinal Pilot Study, Sameh Gomaa, Carly West, Ana Maria Lopez, Tingting Zhan, Max Schnoll, Maysa Abu-Khalaf, Andrew B. Newberg, Kuang-Yi Wen

Department of Medical Oncology Faculty Papers

Background: Estrogen receptor-positive breast cancer is the most common type of breast cancer in postmenopausal women. Aromatase inhibitors (AIs) are the endocrine therapy of choice recommended for these patients. Up to 50% of those treated with an AI develop arthralgia, often resulting in poor adherence and decreased quality of life.

Objective: The study is a single-arm longitudinal pilot study aiming to evaluate the safety, feasibility, acceptability, and potential efficacy of TaiChi4Joint, a remotely delivered 12-week tai chi intervention designed to relieve AI-induced joint pain.

Methods: Women diagnosed with stage 0-III breast cancer who received an AI for at least 2 …

Genomic Features Underlie The Co-Option Of Sva Transposons As Cis-Regulatory Elements In Human Pluripotent Stem Cells, Samantha M Barnada, Andrew Isopi, Daniela Tejada-Martinez, Clément Goubert, Sruti Patoori, Luca Pagliaroli, Mason Tracewell, Marco Trizzino

Department of Biochemistry and Molecular Biology Faculty Papers

Domestication of transposable elements (TEs) into functional cis-regulatory elements is a widespread phenomenon. However, the mechanisms behind why some TEs are co-opted as functional enhancers while others are not are underappreciated. SINE-VNTR-Alus (SVAs) are the youngest group of transposons in the human genome, where ~3,700 copies are annotated, nearly half of which are human-specific. Many studies indicate that SVAs are among the most frequently co-opted TEs in human gene regulation, but the mechanisms underlying such processes have not yet been thoroughly investigated. Here, we leveraged CRISPR-interference (CRISPRi), computational and functional genomics to elucidate the genomic features that underlie SVA domestication …

Targeting Gastrointestinal Cancers With Chimeric Antigen Receptor (Car)-T Cell Therapy, Ross E Staudt, Robert D Carlson, Adam E. Snook

Department of Pharmacology and Experimental Therapeutics Faculty Papers

The immune system is capable of remarkably potent and specific efficacy against infectious diseases. For decades, investigators sought to leverage those characteristics to create immune-based therapies (immunotherapy) that might be far more effective and less toxic than conventional chemotherapy and radiation therapy for cancer. Those studies revealed many factors and mechanisms underlying the success or failure of cancer immunotherapy, leading to synthetic biology approaches, including CAR-T cell therapy. In this approach, patient T cells are genetically modified to express a chimeric antigen receptor (CAR) that converts T cells of any specificity into tumor-specific T cells that can be expanded to …

Partial Treatment Response To Capmatinib In Met-Amplified Metastatic Intrahepatic Cholangiocarcinoma: Case Report & Review Of Literature, Daniel S Lefler, Marni Brisson Tierno, Babar Bashir

Department of Medical Oncology Faculty Papers

Cholangiocarcinoma is a highly morbid gastrointestinal malignancy for which available therapies are limited. Standard of care includes cytotoxic chemotherapies such as gemcitabine, platinum agents, nab-paclitaxel, and fluoropyrimidine analogues. However, tolerability of these regimens varies, and patients who do not tolerate chemotherapy have limited targeted therapies and immunotherapy options. In cholangiocarcinoma, mesenchymal-epithelial transition factor (MET) amplification may present an additional opportunity for a targeted therapeutic approach, especially considering emerging data in non-small cell lung cancer. In this case, we present a metastatic cholangiocarcinoma patient with high-level MET gene amplification for whom capmatinib, a tyrosine kinase inhibitor with activity against c-MET, …

Cancer Vaccines And Immunotherapy For Tumor Prevention And Treatment, Jagmohan Singh, Wilbur Bowne, Adam E. Snook

Kimmel Cancer Center Faculty Papers

In this editorial, we highlight articles published in this Special Issue of Vaccines on "Cancer Vaccines and Immunotherapy for Tumor Prevention and Treatment", recent developments in the field of cancer vaccines, and the potential for immunotherapeutic combinations in cancer care. This issue covers important developments and progress being made in the cancer vaccine field and possible future directions for exploring new technologies to produce optimal immune responses against cancer and expand the arena of prophylactic and therapeutic cancer vaccines for the treatment of this deadly disease.

The Concise Guide To Pharmacology 2021/22: Catalytic Receptors, Stephen Ph Alexander, Doriano Fabbro, Eamonn Kelly, Alistair Mathie, John A Peters, Emma L Veale, Jane F Armstrong, Elena Faccenda, Simon D Harding, Adam J Pawson, Christopher Southan, Jamie A Davies, Annie Beuve, Peter Brouckaert, Clare Bryant, John C Burnett, Richard W Farndale, Andreas Friebe, John Garthwaite, Adrian J Hobbs, Gavin E Jarvis, Michaela Kuhn, David Macewan, Tom P Monie, Andreas Papapetropoulos, Lincoln R Potter, Harald H H W Schmidt, Csaba Szabo, Scott A Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will …

Choline-Sigma-1r As An Additional Mechanism For Potentiation Of Orexin By Cocaine, Jeffrey Barr, Pingwei Zhao, G Cristina Brailoiu, Eugen Brailoiu

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Orexin A, an endogenous peptide involved in several functions including reward, acts via activation of orexin receptors OX₁ and OX₂, Gq-coupled GPCRs. We examined the effect of a selective OX₁ agonist, OXA (17-33) on cytosolic calcium concentration, [Ca²⁺ ]_i, in neurons of nucleus accumbens, an important area in the reward circuit. OXA (17-33) increased [Ca²⁺ ]_i in a dose-dependent manner; the effect was prevented by SB-334867, a selective OX₁ receptors antagonist. In Ca²⁺-free saline, the OXA (17-33)-induced increase in [Ca²⁺ ]_i was not affected by pretreatment …

Point-Of-Care Lung Ultrasound For Covid-19: Findings And Prognostic Implications From 105 Consecutive Patients, Kosuke Yasukawa, Taro Minami, David R Boulware, Ayako Shimada, Ernest A Fischer

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Background: The prognostic value of point-of-care lung ultrasound has not been evaluated in a large cohort of patients with COVID-19 admitted to general medicine ward in the United States. The aim of this study was to describe lung ultrasound findings and their prognostic value in patients with COVID-19 admitted to internal medicine ward.

Method: This prospective observational study consecutively enrolled 105 hospitalized participants with COVID-19 at 2 tertiary care centers. Ultrasound was performed in 12 lung zones within 24 hours of admission. Findings were assessed relative to 4 outcomes: intensive care unit (ICU) need, need for intensive respiratory support, length …

Correspondence Between Perceived Pubertal Development And Hormone Levels In 9-10 Year-Olds From The Adolescent Brain Cognitive Development Study., Megan M Herting, Kristina A Uban, Marybel Robledo Gonzalez, Fiona C Baker, Eric C Kan, Wesley K Thompson, Douglas A Granger, Matthew D Albaugh, Andrey P Anokhin, Kara S Bagot, Marie T Banich, Deanna M Barch, Arielle Baskin-Sommers, Florence J Breslin, B J Casey, Bader Chaarani, Linda Chang, Duncan B Clark, Christine C Cloak, R Todd Constable, Linda B Cottler, Rada K Dagher, Mirella Dapretto, Anthony S Dick, Nico Dosenbach, Gayathri J Dowling, Julie A Dumas, Sarah Edwards, Thomas Ernst, Damien A Fair, Sarah W Feldstein-Ewing, Edward G Freedman, Bernard F Fuemmeler, Hugh Garavan, Dylan G Gee, Jay N Giedd, Paul E A Glaser, Aimee Goldstone, Kevin M Gray, Samuel W Hawes, Andrew C Heath, Mary M Heitzeg, John K Hewitt, Charles J Heyser, Elizabeth A Hoffman, Rebekah S Huber, Marilyn A. Huestis, Luke W Hyde, M Alejandra Infante, Masha Y Ivanova, Joanna Jacobus, Terry L Jernigan, Nicole R Karcher, Angela R Laird, Kimberly H Leblanc, Krista Lisdahl, Monica Luciana, Beatriz Luna, Hermine H Maes, Andrew T Marshall, Michael J Mason, Erin C Mcglade, Amanda S Morris, Bonnie J Nagel, Gretchen N Neigh, Clare E Palmer, Martin P Paulus, Alexandra S Potter, Leon I Puttler, Nishadi Rajapakse, Kristina Rapuano, Gloria Reeves, Perry F Renshaw, Claudiu Schirda, Kenneth J Sher, Chandni Sheth, Paul D Shilling, Lindsay M Squeglia, Matthew T Sutherland, Susan F Tapert, Rachel L Tomko, Deborah Yurgelun-Todd, Natasha E Wade, Susan R B Weiss, Robert A Zucker, Elizabeth R Sowell

Institute of Emerging Health Professions Faculty Papers

Aim: To examine individual variability between perceived physical features and hormones of pubertal maturation in 9-10-year-old children as a function of sociodemographic characteristics.

Methods: Cross-sectional metrics of puberty were utilized from the baseline assessment of the Adolescent Brain Cognitive Development (ABCD) Study—a multi-site sample of 9–10 year-olds (n = 11,875)—and included perceived physical features via the pubertal development scale (PDS) and child salivary hormone levels (dehydroepiandrosterone and testosterone in all, and estradiol in females). Multi-level models examined the relationships among sociodemographic measures, physical features, and hormone levels. A group factor analysis (GFA) was implemented to extract latent variables of pubertal …

The Role Of Mirnas, Mirna Clusters, And Isomirs In Development Of Cancer Stem Cell Populations In Colorectal Cancer., Victoria A Stark, Caroline O B Facey, Vignesh Viswanathan, Bruce M Boman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

MicroRNAs (miRNAs or miRs) have a critical role in regulating stem cells (SCs) duringdevelopment and altered expression can cause developmental defects and/or disease. Indeed,aberrant miRNA expression leads to wide-spread transcriptional dysregulation which has beenlinked to many cancers. Mounting evidence also indicates a role for miRNAs in the developmentof the cancer SC (CSC) phenotype. Our goal herein is to provide a review of: (i) current researchon miRNAs and their targets in colorectal cancer (CRC), and (ii) miRNAs that are differentiallyexpressed in colon CSCs. MicroRNAs can work in clusters or alone when targeting different SC genesto influence CSC phenotype. Accordingly, we discuss …

Fatal Case Of Newborn Lassa Fever Virus Infection Mimicking Late Onset Neonatal Sepsis: A Case Report From Northern Nigeria, Taofik Oluwaseun Ogunkunle, Surajudeen Oyeleke Bello, Chinwe Immaculata Anderson, Rashida Musa, Rasaq Olaosebikan, Abdulazeez Imam

Department of Pharmacology and Experimental Therapeutics Faculty Papers

BACKGROUND: Lassa fever is a zoonotic viral infection endemic to the West Africa countries. It is highly fatal during pregnancy and as such reports of neonatal onset Lassa fever infections are rare in scientific literature. We report a fatal case of Lassa fever in a 26-day-old neonate mimicking the diagnosis of late-onset neonatal sepsis.

CASE PRESENTATION: The patient is a 26-day-old neonate who was admitted with a day history of fever, poor feeding, pre-auricular lymphadenopathy and sudden parental death. He was initially evaluated for late onset neonatal sepsis. He later developed abnormal bleeding and multiple convulsions while on admission, prompting …

Twice-Daily Doravirine Overcomes The Interaction Effect From Once-Weekly Rifapentine And Isoniazid In Healthy Volunteers., Edwin Lam, Joseph Schaefer, Richard Zheng, Tingting Zhan, Walter K. Kraft

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Doravirine (DOR) is a non‐nucleoside reverse transcriptase inhibitor indicated for the treatment of human immunodeficiency virus‐1 (HIV‐1). Its use in combination with rifapentine (RPT), an anti‐tuberculosis antibiotic, may reduce the exposure of DOR compromising viral suppression in those living with HIV‐1 co‐infected with tuberculosis. We conducted a prospective, phase I, open label, two‐period, fixed sequence, drug interaction study to evaluate the effect of once‐weekly RPT and isoniazid (INH) on the pharmacokinetics of DOR in healthy volunteers. DOR 100 mg was administered alone twice‐daily for 4 days in period 1. In period 2, once‐weekly RPT+INH was co‐administered with multiple doses of …

Vancomycin In Peritoneal Dialysis: Clinical Pharmacology Considerations In Therapy., Edwin Lam, Yi Ting Kayla Lien, Walter K. Kraft, Beth Piraino, Valvanera Vozmediano, Stephan Schmidt, Jingjing Zhang

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Intraperitoneal vancomycin is the first-line therapy in the management of peritoneal dialysis (PD)-related peritonitis. However, due to the paucity of data, vancomycin dosing for peritonitis in patients on automated peritoneal dialysis (APD) is empiric and based on clinical experience rather than evidence. Studies in continuous ambulatory peritoneal dialysis (CAPD) patients have been used to provide guidelines for dosing and are often extrapolated for APD use, but it is unclear whether this is appropriate. This review summarizes the available pharmacokinetic data used to inform optimal dosing in patients on CAPD or APD. The determinants of vancomycin disposition and pharmacodynamic effects are …

Alkalinizing Agents: A Review Of Prescription, Over-The-Counter, And Medical Food Supplements., Karen L. Stern, Noah Canvasser, Michael Borofsky, Vanessa M. Gleason, Guido Kamphuis, Marawan M. El Tayeb, Ryan Hsi, Kymora B. Scotland

Jefferson Hospital Staff Papers and Presentations

Introduction

Kidney stones affect 1 in every 11 people in the United States each year. There is a significant high recurrence rate without a stone prevention protocol. Alkali citrate is beneficial in decreasing stone recurrence, but due to the cost and gastrointestinal side effects there is a low adherence rate. This study aims to serve as a review of some of the most commonly used alkalizing over‐ the‐ counter supplements that are advertised to prevent and treat kidney stones.

Methods

Data was gathered by a comprehensive online literature search and company inquiries for kidney stone prevention supplements. An additional informal …

No Meaningful Drug Interactions With Doravirine, Lamivudine And Tenofovir Disoproxil Fumarate Co-Administration., Matt S. Anderson, Jocelyn Gilmartin, Li Fan, Ka Lai Yee, Walter K. Kraft, Ilias Triantafyllou, Christina Reitmann, Ying Guo, Rachael Liu, Marian Iwamoto

Department of Pharmacology and Experimental Therapeutics Faculty Papers

BACKGROUND: Doravirine (DOR) is a novel non-nucleoside reverse transcriptase inhibitor available as a single tablet and a three-drug combination with lamivudine (3TC) and tenofovir disoproxil fumarate (TDF) to treat HIV-1 infection. These analyses assessed pharmacokinetic (PK) interactions with co-administration.

METHODS: Two trials were conducted. Study 1: two-period, fixed-sequence; 8 healthy participants; Period 1, DOR 100 mg followed by ≥7-day washout; Period 2, TDF 300 mg once daily for 18 days, co-administration of DOR 100 mg on day 14. Study 2: three-period, crossover, 15 healthy participants; Treatment A, DOR 100 mg; Treatment B, 3TC 300 mg + TDF 300 mg; Treatment …

Drug Interactions Between Direct-Acting Oral Anticoagulants And Calcineurin Inhibitors During Solid Organ Transplantation: Considerations For Therapy, Edwin Lam, Babar Bashir, Mark Chaballa, Walter K. Kraft

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Introduction: There is a high incidence of venous thromboembolism (VTE) in solid organ transplant recipients. The safety and efficacy of direct-acting oral anticoagulants (DOAC) have been well established in clinical practice for the prevention and treatment of VTE in broad populations. However, the management of VTE in the setting of solid organ transplantation remains a challenge to clinicians due to limited evidence of DOAC usage with calcineurin inhibitors.

Areas covered: The current literature available on the pharmacokinetic-pharmacodynamic interaction between DOACs and calcineurin inhibitors is presented. A comprehensive review was undertaken using PubMed, Embase, drug product labeling, and drug …

Silencing The Guca2a-Gucy2c Tumor Suppressor Axis In Cin, Serrated, And Msi Colorectal Neoplasia., Babar Bashir, Dante J. Merlino, Jeff A. Rappaport, Esteban Gnass, Juan P. Palazzo, Ying Feng, Eric R R. Fearon, Adam E. Snook, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Colorectal cancers (CRCs) initiate through distinct mutations, including in APC pathway components leading to tubular adenomas (TAs); in BRAF, with epigenetic silencing of CDX2, leading to serrated adenomas (SAs); and in the DNA mismatch repair machinery driving microsatellite instability (MSI). Transformation through the APC pathway involves loss of the hormone GUCA2A that silences the tumor-suppressing receptor GUCY2C. Indeed, oral hormone replacement is an emerging strategy to reactivate GUCY2C and prevent CRC initiation and progression. Moreover, retained expression by tumors arising from TAs has established GUCY2C as a diagnostic and therapeutic target to prevent and treat metastatic CRC. Here, we defined …

Split Tolerance Permits Safe Ad5-Gucy2c-Padre Vaccine-Induced T-Cell Responses In Colon Cancer Patients., Adam E. Snook, Trevor R. Baybutt, Bo Xiang, Tara S. Abraham, John C. Flickinger, Terry Hyslop, Tingting Zhan, Walter K. Kraft, Takami Sato, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Background: The colorectal cancer antigen GUCY2C exhibits unique split tolerance, evoking antigen-specific CD8+, but not CD4+, T-cell responses that deliver anti-tumor immunity without autoimmunity in mice. Here, the cancer vaccine Ad5-GUCY2C-PADRE was evaluated in a first-in-man phase I clinical study of patients with early-stage colorectal cancer to assess its safety and immunological efficacy.

Methods: Ten patients with surgically-resected stage I or stage II (pN0) colon cancer received a single intramuscular injection of 1011 viral particles (vp) of Ad5-GUCY2C-PADRE. Safety assessment and immunomonitoring were carried out for 6 months following immunization. This trial employed continual monitoring of both efficacy and toxicity …

Pharmacokinetics Of Ketamine At Dissociative Doses In An Adult Patient With Refractory Status Asthmaticus Receiving Extracorporeal Membrane Oxygenation Therapy., Edwin Lam, Ankit K. Rochani, Gagan Kaushal, Brandi N. Thoma, Julian Tanjuakio, Frances Mae West, Hitoshi Hirose

Department of Pharmacology and Experimental Therapeutics Faculty Papers

PURPOSE: First-line management of severe asthma exacerbations include the use of inhaled short-acting β-agonists, anticholinergics, and systemic corticosteroids. Continuous intravenous ketamine given at dissociative doses may be a pharmacologic option in patients who are intubated with life-threatening severe bronchospasm unresponsive to standard therapy. We describe the case of a 44-year-old man admitted to the intensive care unit for status asthmaticus requiring intubation and mechanical ventilation.

METHODS: The patient developed severe refractory hypercapnic respiratory failure necessitating additional respiratory support with veno-venous extracorporeal membrane oxygenation (ECMO) therapy. Ketamine treatment was initiated at 0.5 mg/kg/h continuous infusion on the day of admission for …

Apixaban Discontinuation Prior To Major Surgery: Results From A Prospective Single Center Study, Edwin Lam, Luis Eraso, Taki Galanis, Walter K. Kraft, Geoffrey Ouma, Lynda Thomson, Eugene Viscusi, Douglas Stickle, Jerald Z. Gong, Suzanne Adams, Geno Merli

Department of Pharmacology and Experimental Therapeutics Posters

Primary Objective

• Estimate the proportion of patients who achieve a plasma apixaban concentration of/mL following at least 48 hours of discontinuation prior to surgery or invasive procedure

Secondary Objective

• Perioperative and follow up arterial or venous thromboembolic events, major bleeding, clinically significant non-major bleeding complications. Correlation of apixaban anti-Factor Xa (FXa) activity and plasma apixaban concentrations at pre-admission and prior to surgery

Pharmacological And Non-Pharmacological Treatments For The Neonatal Abstinence Syndrome (Nas)., A. K. Mangat, G. M. Schmölzer, W. K. Kraft

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Neonatal abstinence syndrome is defined by signs and symptoms of withdrawal that infants develop after intrauterine maternal drug exposure. All infants with documented in utero opioid exposure, or a high pre-test probability of exposure should have monitoring with a standard assessment instrument such as a Finnegan Score. A Finnegan score of >8 is suggestive of opioid exposure, even in the absence of declared use during pregnancy. At least half of infants in most locales can be treated without the use of pharmacologic means. For this reason, symptom scores will drive the decision for pharmacologic therapy. Nevertheless, all infants, regardless of …