Medicine and Health Sciences Commons^™

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 …

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 …

Hoxa9 Overexpression Contributes To Stem Cell Overpopulation That Drives Development And Growth Of Colorectal Cancer, Brian Osmond, Caroline O.B. Facey, Chi Zhang, Bruce M. Boman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

HOX proteins are transcription factors that regulate stem cell (SC) function, but their role in the SC origin of cancer is under-studied. Aberrant expression of HOX genes occurs in many cancer types. Our goal is to ascertain how retinoic acid (RA) signaling and the regulation of HOXA9 expression might play a role in the SC origin of human colorectal cancer (CRC). Previously, we reported that aldehyde dehydrogenase (ALDH) and other RA pathway components are co-expressed in colonic cancer SCs (CSCs) and that overpopulation of ALDH-positive CSCs occurs during colon tumorigenesis. Our hypothesis is RA signaling regulates HOXA9 expression, and dysregulated …

Age Moderates The Effect Of Injury Severity On Functional Trajectories In Traumatic Brain Injury: A Study Using The Nidilrr Traumatic Brain Injury Model Systems National Dataset., Laraine Winter, Janell L Mensinger, Helene J Moriarty, Keith M Robinson, Michelle Mckay, Benjamin E Leiby

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Age is a risk factor for a host of poor outcomes following traumatic brain injury (TBI), with some evidence suggesting that age is also a source of excess disability. We tested the extent to which age moderates the effect of injury severity on functional trajectories over 15 years post injury. Data from 11,442 participants from the 2020 National Institute of Disability and Independent Living Rehabiitation Research (NIDILRR) Traumatic Brain Injury Model Systems (TBIMS) National Dataset were analyzed using linear mixed effects models. Injury severity was operationally defined using a composite of Glasgow Coma Scale scores, structural imaging findings, and the …

T-Cell Responses To Immunodominant Listeria Epitopes Limit Vaccine-Directed Responses To The Colorectal Cancer Antigen, Guanylyl Cyclase C, John C. Flickinger, Jagmohan Singh, Yanki Yarman, Robert D Carlson, Joshua Barton, Scott A Waldman, Adam E. Snook

Department of Pharmacology and Experimental Therapeutics Faculty Papers

The Gram-positive bacterium Listeria monocytogenes (Lm) is an emerging platform for cancer immunotherapy. To date, over 30 clinical trials have been initiated testing Lm cancer vaccines across a wide variety of cancers, including lung, cervical, colorectal, and pancreatic. Here, we assessed the immunogenicity of an Lm vaccine against the colorectal tumor antigen GUCY2C (Lm-GUCY2C). Surprisingly, Lm-GUCY2C vaccination did not prime naïve GUCY2C-specific CD8+ T-cell responses towards the dominant H-2Kd-restricted epitope, GUCY2C254-262. However, Lm-GUCY2C produced robust CD8+ T-cell responses towards Lm-derived peptides suggesting that GUCY2C254-262 peptide may be subdominant to Lm-derived peptides. Indeed, incorporating immunogenic Lm peptides into an adenovirus-based GUCY2C …

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 …

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 …

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 …

Mobilizing Toxins For Cancer Treatment: Historical Perspectives And Current Strategies., Jessica Kopenhaver, Robert D Carlson, Adam E Snook

Department of Pharmacology and Experimental Therapeutics Faculty Papers

The level of complexity in a disease like cancer presents a number of challenges for effective treatment development, which require significant innovation to overcome [...].

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 …

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 …

Non-Thermal Plasma-Induced Immunogenic Cell Death In Cancer: A Topical Review., Marian Khalili, Lynsey Daniels, Abraham Lin, Fred C. Krebs, Adam E. Snook, Sander Bekeschus, Wilbur B. Bowne, Vandana Miller

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Recent advances in biomedical research in cancer immunotherapy have identified the use of an oxidative stress-based approach to treat cancers, which works by inducing immunogenic cell death (ICD) in cancer cells. Since the anti-cancer effects of non-thermal plasma (NTP) are largely attributed to the reactive oxygen and nitrogen species that are delivered to and generated inside the target cancer cells, it is reasonable to postulate that NTP would be an effective modality for ICD induction. NTP treatment of tumors has been shown to destroy cancer cells rapidly and, under specific treatment regimens, this leads to systemic tumor-specific immunity. The translational …

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 …

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 …

Advances In Chimeric Antigen Receptor T-Cell Therapies For Solid Tumors., Trevor R. Baybutt, John C. Flickinger, Ellen M. Caparosa, Adam E. Snook

Department of Pharmacology and Experimental Therapeutics Faculty Papers

In 2017, the US Food and Drug Administration approved the first two novel cellular immunotherapies using synthetic, engineered receptors known as chimeric antigen receptors (CARs), tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta), expressed by patient-derived T cells for the treatment of hematological malignancies expressing the B-cell surface antigen CD19 in both pediatric and adult patients. This approval marked a major milestone in the use of antigen-directed "living drugs" for the treatment of relapsed or refractory blood cancers, and with these two approvals, there is increased impetus to expand not only the target antigens but also the tumor types that can be …

Health Care Evolves From Reactive To Proactive., Scott A. Waldman, Andre Terzic

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Decoding health and disease pathways drives healthcare evolution. Historically, therapeutic paradigms have relied on interventions that mitigate symptoms of established diseases. Increasingly, molecular insights into pathophysiology now provide unprecedented opportunities to offer curative solutions or even prevent disease and thereby secure longitudinal wellness. These opportunities extend past individual patients to entire populations and geographies. Moreover, they optimize prospective healthspan across lifespan. Linking discovery science and its translatable innovations beyond reactive disease intervention to proactive prevention will maximize society’s returns creating the greatest benefit for the greatest number of people globally.

The Anti-Cancer Effect Of Retinoic Acid Signaling In Crc Occurs Via Decreased Growth Of Aldh+ Colon Cancer Stem Cells And Increased Differentiation Of Stem Cells, Shirin R. Modarai, Anindita Gupta, Lynn M. Opdenaker, Ryan Kowash, Gabriel Masters, Vignesh Viswanathan, Tao Zhang, Jeremy Z. Fields, Bruce M. Boman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Background: Tumorigenesis is driven by stem cell (SC) overpopulation. BecauseALDH is both a marker for SCs in many tissues and a key enzyme in retinoid acid (RA)signaling, we studied RA signaling in normal and malignant colonic SCs.Hypothesis: RA signaling regulates growth and differentiation of ALDH+ colonicSCs dysregulation of RA signaling contributes to SC overpopulation and colorectalcancer (CRC) development.Methods: We analyzed normal and malignant colonic tissues and CRC cell linesto see if retinoid receptors (RXR &RAR) are exclusively expressed in ALDH+ SCs,and if RA signaling changes during CRC development. We determined whether RAsignaling regulates cancer SC (CSC) proliferation, differentiation, sphere formation,and …

Listeria Monocytogenes As A Vector For Cancer Immunotherapy: Current Understanding And Progress, John C. Flickinger, Ulrich Rodeck, Adam E. Snook

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Listeria monocytogenes, a Gram-positive facultative anaerobic bacterium, is becoming a popular vector for cancer immunotherapy. Indeed, multiple vaccines have been developed utilizing modified Listeria as a tool for generating immune responses against a variety of cancers. Moreover, over a dozen clinical trials testing Listeria cancer vaccines are currently underway, which will help to understand the utility of Listeria vaccines in cancer immunotherapy. This review aims to summarize current views on how Listeria-based vaccines induce potent antitumor immunity and the current state of Listeria-based cancer vaccines in clinical trials. © 2018 by the authors. Licensee MDPI, Basel, Switzerland.

The Guanylate Cyclase C-Cgmp Signaling Axis Opposes Intestinal Epithelial Injury And Neoplasia., Jeffrey A. Rappaport, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Guanylate cyclase C (GUCY2C) is a transmembrane receptor expressed on the luminal aspect of the intestinal epithelium. Its ligands include bacterial heat-stable enterotoxins responsible for traveler's diarrhea, the endogenous peptide hormones uroguanylin and guanylin, and the synthetic agents, linaclotide, plecanatide, and dolcanatide. Ligand-activated GUCY2C catalyzes the synthesis of intracellular cyclic GMP (cGMP), initiating signaling cascades underlying homeostasis of the intestinal epithelium. Mouse models of GUCY2C ablation, and recently, human populations harboring GUCY2C mutations, have revealed the diverse contributions of this signaling axis to epithelial health, including regulating fluid secretion, microbiome composition, intestinal barrier integrity, epithelial renewal, cell cycle progression, responses …

Evaluating Comfort Measures For Commonly Performed Painful Procedures In Pediatric Patients., Sana Dastgheyb, Keith Fishlock, Constantine Daskalakis, Jami Kessel, Paul Rosen

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Introduction: Management of pediatric pain from medical procedures is of great importance for improving both patient care and experience. In this study, we investigated methods of managing acute pain in infants and children by studying the correlation between the number of attempts to complete painful procedures, given different comfort measures.

Methods: The study is a retrospective review of 74,276 procedures performed at two pediatric hospitals in an integrated academic children's health system between 2013 and 2016. We compared three comfort measures most frequently offered: positions of comfort (POC), distraction (DIST), and pharmacological (PHARM). These methods were compared in the setting …

Human Gucy2c-Targeted Chimeric Antigen Receptor (Car)-Expressing T Cells Eliminate Colorectal Cancer Metastases., Michael S. Magee, Tara S. Abraham, Trevor R. Baybutt, John C. Flickinger, Natalie A. Ridge, Glen P Marszalowicz, Priyanka Prajapati, Adam R. Hersperger, Scott A. Waldman, Adam E. Snook

Department of Pharmacology and Experimental Therapeutics Faculty Papers

One major hurdle to the success of adoptive T-cell therapy is the identification of antigens that permit effective targeting of tumors in the absence of toxicities to essential organs. Previous work has demonstrated that T cells engineered to express chimeric antigen receptors (CAR-T cells) targeting the murine homolog of the colorectal cancer antigen GUCY2C treat established colorectal cancer metastases, without toxicity to the normal GUCY2C-expressing intestinal epithelium, reflecting structural compartmentalization of endogenous GUCY2C to apical membranes comprising the intestinal lumen. Here, we examined the utility of a human-specific, GUCY2C-directed single-chain variable fragment as the basis for a CAR construct targeting …

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 …