Medicine and Health Sciences Commons^™

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.