Chemicals and Drugs Commons^™

Spravato® Fda-Approved As Monotherapy For Adults With Treatment-Resistant Depression, Rileigh Rahrig, Kennedy Kosikowski, Haylee Whyde, Kiley Devoll, Allie Honigford, Macy Davis, Joshua Honaker, Samantha Mccord, Manoranjan D'Souza

Pharmacy and Wellness Review

Treatment-resistant depression (TRD) is a challenging and possibly life-threatening condition that affects millions of people worldwide. Patients with major depressive disorder (MDD) are diagnosed with TRD once they have tried and failed to respond to two antidepressant treatments at the maximum dose for a full trial of six to eight weeks. Most traditional antidepressant therapies work by increasing the levels of monoamine neurotransmitters such as dopamine, serotonin, and norepinephrine in the brain. These medications have a delayed onset of action, ranging from two to eight weeks, and often fail to relieve depressive symptoms in a patient with TRD. Therefore, targeting …

Tacrolimus Dosing In Liver Transplant Recipients Using Phenotypic Personalized Medicine: A Phase 2 Randomized Clinical Trial, Jeffrey Khong, Megan Lee, Curtis Warren, Un Kim, Sergio Duarte, Kenneth Andreoni, Sunaina Shrestha, Mark Johnson, Narendra Battula, Danielle Mckimmy, Thiago Beduschi, Ji-Hyun Lee, Derek Li, Chih-Ming Ho, Ali Zarrinpar

Department of Surgery Faculty Papers

Tacrolimus is the most commonly used immunosuppression drug after solid organ transplantation; however, its dosing is challenging due to substantial inter-individual variability, often resulting in blood levels that deviate from the target therapeutic range. We explored whether a dynamically customized, phenotypic-outcome-guided drug dosing method could improve maintenance of drug trough levels within pre-determined target ranges, focusing on tacrolimus immediately after liver transplantation. This single-center, partially blinded, completed clinical trial involved 62 adults undergoing liver transplantation, block randomized into parallel groups: standard-of-care (SOC) clinician-determined or Phenotypic Personalized Medicine (PPM)-guided tacrolimus dosing. The primary outcome was percentage of post-transplant days with large …

Reducing Premedication Use With Intravenous Iron In The Outpatient Setting, Tara Rakiewicz, Liam Heneghan, Mark Attilio, Ruben Rhoades, Michael Zimmerman, Matthew Tucker, Brianna Costello, Adam Binder, Tanya Thomas

Health Equity and Quality Improvement (HEQI) Summit

Background

• Intravenous (IV) formulations of iron are safe, quick, easy to administer, and are indicated in patients with Iron Deficiency.
• Prior formulations of IV iron were associated with anaphylaxis and have since been removed from the market -- healthcare workers remain anxious about their potential for reactions
• Rate of anaphylactic reactions are about 1 in 200,000 infusions
• Current IV formulations available can be associated with a complement mediated, pseudo-allergy, that presents with flushing, myalgia/arthralgia, and chest pressure. Reactions are dependent on infusion rate and improve after stopping the infusion.
• Premedication with acetaminophen and diphenhydramine are often ordered for IV iron …

Chronic Inflammatory Pain And Chronic Thc Vapor Inhalation Alter Midbrain Neuronal Activity, Leslie K. Kelley, Nicholas W. Gilpin, Jason W. Middleton

School of Medicine Faculty Publications

In an effort to reduce reliance on opioids for the treatment of pain in the clinic, ongoing work is testing the utility of cannabinoid drugs as a potential alternative for treatment of chronic pain. We tested chronic delta-9 tetrahydrocannabinol (THC) vapor inhalation effects on intrinsic and synaptic properties of ventrolateral periaqueductal gray (vlPAG) neurons in male and female rats treated with complete Freund's adjuvant (CFA). We report that chronic THC vapor inhalation modulates intrinsic and synaptic properties of vlPAG neurons, including reductions in action potential firing rate and spontaneous inhibitory synaptic transmission in males, and that these effects occur specifically …

Probing Binding And Allosteric Mechanisms Of The Kras Interactions With Monobodies And Affimer Proteins : Ensemble-Based Mutational Profiling And Thermodynamic Analysis Of Binding Energetics And Allostery Reveal Diversity Of Functional Hotspots And Cryptic Pockets Linked By Conserved Communication Network, Mohammed Alshahrani, Vedant Parikh, Brandon Foley, Guang Hu, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

KRAS, a historically "undruggable" oncogenic driver, has eluded targeted therapies due to its lack of accessible binding pockets in its active state. This study investigates the conformational dynamics, binding mechanisms, and allosteric communication networks of KRAS in complexes with monobodies (12D1, 12D5) and affimer proteins (K6, K3, K69) to characterize the binding and allosteric mechanisms and hotspots of KRAS binding. Through molecular dynamics simulations, mutational scanning, binding free energy analysis and network-based analyses, we identified conserved allosteric hotspots that serve as critical nodes for long-range communication in KRAS. Key residues in β-strand 4 (F78, L80, F82), α-helix 3 (I93, H95, …

Chronic Inflammation: The Link Between A High Added Sugar Diet And Disease, Anna Collins

Senior Honors Theses

The modern diet includes many processed foods that contain added sugars, resulting in a significant increase in daily glucose and fructose consumption. Considering this, there is an increased effort to uncover the effects of excess sugar intake on the body’s health and metabolism. Strong evidence supports the connection between a high added sugar diet and the presence of chronic, low-grade inflammation due to cellular distress and metabolic dysfunction. Prolonged inflammatory responses are linked to tissue damage and the development of various metabolic diseases that are prevalent in modern society, such as obesity, fatty liver disease, cardiovascular disease, and type 2 …

Ovarian Cancer G Protein-Coupled Receptor-1 Signaling Bias Dictates Anti-Contractile Effect Of Benzodiazepines On Airway Smooth Muscle, Dominic R. Villalba, Arun K. Jannu, Elham Javed, Isha Dandekar, Ruping Wang, Deepak A. Deshpande, Steven S. An, Reynold A. Panettieri, Dale D. Tang, Raymond B. Penn, Ajay P. Nayak

Center for Translational Medicine Faculty Papers

BACKGROUND: We recently reported that the ovarian cancer G protein-coupled receptor-1 (OGR1) can be pharmacologically biased with specific benzodiazepines to couple with distinct heterotrimeric G proteins in human airway smooth muscle (ASM) cells. Lorazepam stimulated both G

METHODS: Models of histamine (His) -stimulated contraction included imaging of ex vivo human precision cut lung slices (hPCLS) and Magnetic Twisting Cytometry (MTC) analysis of human ASM cell stiffness. To explore mechanisms of regulation, we examined effects on myosin light chain (pMLC) phosphorylation and PKA activity in primary human ASM cultures, as well as actin cytoskeleton integrity as defined by changes in the …

Physiologically Based And Population Pharmacokinetic Modeling Of Midazolam In Children With Obesity Using Real-World Data, Sean Mccann, Victória E. Helfer, Stephen J. Balevic, William J. Muller, John N. Van Den Anker, Amira Al-Uzri, Marisa L. Meyer, Sarah G. Anderson, Sitora Turdalieva, Andrea N. Edginton, Daniel Gonzalez, Best Pharmaceuticals For Children Act Pediatric Trials Network Steering Committee

Department of Pediatrics Faculty Papers

Children represent a highly complex and variable population for treatment, including interindividual differences in drug dose-exposure. Midazolam has been used as a sedative for hospitalized children on- and off-label; however, factors affecting interindividual variability (IIV) in observed clearance for this population are not fully understood and can result in extreme under- or overexposure. Obesity has been described as a significant influence on midazolam in adolescents, which could potentially alter drug exposure. The goal of this study was to use two modeling strategies to evaluate dose-exposure of midazolam in children with and without obesity. Population pharmacokinetic modeling assessed whether measures of …

Validating The Ability Of Iag933 To Block The Interaction Of Yap1 And Tead In Ovarian Cancer Cells, Alex Sage

Theses & Dissertations

Ovarian cancer is the most common and deadliest gynecologic malignancy. Approximately 40% of ovarian cancer patients exhibit chemoresistance after receiving initial treatment in the form of neoadjuvant chemotherapy or interval debulking surgery, of which YAP1 (Yes-associated protein 1) has been implicated in enhancing the resistance of ovarian cancer to Cisplatin and Taxol.^1,2. This highlights the need to develop new therapeutic strategies that target the Hippo pathway to overcome resistance to traditional therapies.

YAP1 is a protein that acts as a transcription coregulator, promoting the transcription of genes involved in cellular proliferation and suppressing apoptotic genes. It is a …

A Chemical Investigation: Monitoring Cannabidiol Concentration In The Presence Of Ionic Liquids, Hannah E. Mabie

Honors Theses

Cannabidiol (CBD) is a non-psychoactive cannabinoid from the plant, Cannabis sativa. CBD’s structure degrades over time and other minor cannabinoids are formed when in contact with organic solvents. This is a growing area of interest due to the Agriculture Improvement Act (The Farm Bill) in 2018, which led to growing marijuana consumption and increased CBD markets. Monitoring the concentration of CBD can be used by forensic investigators and researchers to determine how CBD interacts with solvents, like ionic liquids. In this study, different ionic liquids were used to determine the best route of solubility and if choline based ionic liquids …

Investigating The Cytotoxic Effects Of Amino Acid-Based Ionic Liquids And Peg-Pla Nanoparticles On Mcf10a Human Breast Epithelial Cells For Drug Delivery Applications, Ella C. Mertins

Honors Theses

This study investigates the cytotoxic effects of polyethylene glycol-polylactic acid (PEG-PLA) nanoparticles (NPs) both bare and coated with choline-based ionic liquids (ILs) on MCF10A human breast epithelial cells. The goal was to evaluate how IL-modified NPs influence cell viability at varying concentrations and to assess their potential as drug delivery systems. Three choline-based ILs, Choline-L-Asparagine 1:1, Choline-DL-Isoleucinate 1:1, and Choline-L-Leucinate 1:1, were used as surface coatings for PEG-PLA NPs. Additionally, the ILs were tested independently to establish a baseline for their cytotoxicity. Using a luminescent ATP-based viability assay following the treatment of MCF10A cells, the ILs were found to be …

Menthalactone From Mentha Piperita L., A Monocot-Selective Bioherbicide, Adam Soltani

Honors Theses

The challenge of managing invasive weed species continues to affect the agricultural industry, presenting ecological, economic, and agronomic hurdles that lead to over 100 billion USD in annual crop losses globally. One such concern is the management of Agrostis stolonifera L., commonly known as creeping bentgrass, particularly due to its ability to form hybrids. This scenario underscores the urgent need for innovative, effective, and environmentally sustainable herbicides, steering the focus toward natural substances as potential candidates. We report here a promising natural lactone, commonly known as menthalactone, which is derived from Mentha piperita L. Its phytotoxic activity was assessed against …

Reducing The Percentage Of Intubation Time On Continuous Infusion Midazolam, Arsemen Brown, Emily Highsmith, Michelle Horng

Advances in Cancer Education and Quality Improvement

This quality improvement study was conducted at a comprehensive cancer care center with the aim to decrease the percentage of on continuous infusion (CI) midazolam by 30% by May 5, 2023. The pre-intervention and post-intervention data collection phases occurred from January 1, 2022, to October 31, 2022, and March 7, 2023, to May 5, 2023, respectively. Sedation was assessed utilizing the Richmond Agitation and Sedation Scale (RASS), and delirium was assessed utilizing the Intensive Care Delirium Screening Checklist (ICDSC). A sedation pathway and associated educational materials were developed by a multidisciplinary team and frontline staff. Interventions in the sedation pathway …

Integrating Positive Psychology And Spirituality To Foster Meaning And Well-Being In Older Adults, Crystal Morris

Adultspan Journal

This perspective article explores the integration of positive psychology interventions (PPIs) and spirituality in therapy to foster meaning and well-being in older adults. It highlights exercises such as the positive introduction, positive legacy, character strengths, mindfulness, mindful-based yoga, and a manifestation prayer journaling. The interventions presented are tools to support older adults that may experience depression, difficult life transitions, and the search for renewed meaning. Therapists who integrate PPIs and spirituality into therapy can promote a holistic, non-pathological approach to treatment.

Impaired Dnajb2 Response To Heat Shock In Fibroblasts From A Neuropathy Patient With Dnajb2/Hsj1 Mutation: Cystamine As A Potential Therapeutic Intervention, Raj K. Pradhan, Nikolas G. Kinney, Brigid K. Jensen, Hristelina Ilieva

Farber Institute for Neuroscience Faculty Papers

Background and Objectives: Neuropathy is a debilitating disorder characterized by peripheral nerve dysfunction and damage to sensory, motor, and autonomic neurons and their axons. While homozygous mutations in DNAJB2/HSJ1 have been linked to early-onset neuropathy, a heterozygous DNAJB2 c.823+6C>T was discovered in an adult patient with severe sensory–motor polyneuropathy. This mutation is predicted to affect both isoforms of the protein. DNAJB2 (HSP40), a key member of the heat shock protein family, plays a critical role in cellular protection and stress, including response to heat shock. DNAJB2 traffics unfolded proteins to another heat shock protein, HSP70, and activates its ATPase …

Sirt6 Deficiency Promotes Senescence And Age-Associated Intervertebral Disc Degeneration In Mice, Pranay Ramteke, Bahiyah Watson, Mallory Toci, Victoria Tran, Shira N Johnston, Maria Tsingas, Ruteja Barve, Ramkrishna Mitra, Richard Loeser, John Collins, Makarand Risbud

Department of Orthopaedic Surgery Faculty Papers

Intervertebral disc degeneration is a major risk factor contributing to chronic low back and neck pain. While the etiological factors for disc degeneration vary, age is still one of the most important risk factors. Recent studies have shown the promising role of SIRT6 in mammalian aging and skeletal tissue health, however its role in the intervertebral disc health remains unexplored. We investigated the contribution of SIRT6 to disc health by studying the age-dependent spinal phenotype of mice with conditional deletion of Sirt6 in the disc (Acan^CreERT2; Sirt6^fl/fl). Histological studies showed a degenerative phenotype in knockout mice …

Exploring Cisd1 As A Multifaceted Biomarker In Cancer: Implications For Diagnosis, Prognosis, And Immunotherapeutic Response, Caiyue Li, Zhipin Liang, Gabrielle Vontz, Connor Kent, Wenbo Ma, Lei Liu, Riya Dahal, Jovanny Zabaleta, Guoshuai Cai, Jia Zhou, Huangen Ding, Qiang Shen

School of Graduate Studies Faculty Publications

CISD1, an outer mitochondrial membrane iron-sulfur cluster protein, regulates intracellular iron levels, oxidative stress, and mitochondrial dynamics, playing critical roles in cellular bioenergetics and redox homeostasis. Although CISD1 has been identified as a prognostic biomarker in specific cancers, its broader implications in tumorigenesis, cancer progression, and immunotherapy remain unclear. Given the heterogeneity of cancer and the need for robust biomarkers across cancers, this study conducts the first comprehensive pan-cancer analysis of CISD1 by evaluating its roles in cancer and treatment. We obtained and analyzed data from databases including TCGA, GTEx, THPA, GEPIA2.0, SangerBox, cBioPortal, TIMER2.0, CAMOIP, DAVID, SRPLOT, and TISIDB. …

Rationally Designed Pentapeptide Analogs Of Aβ19-23 Fragment As Potent Inhibitors Of Aβ42 Aggregation, Sachin B. Baravkar, Yan Lu, Qi Zhao, Hongying Peng, Weilie Zhou, Song Hong

School of Medicine Faculty Publications

Amyloid beta (Aβ42 and Aβ40) aggregation, along with neurofibrillary tangles, is one of the major neurotoxic events responsible for the onset of Alzheimer's disease. Many potent peptide-based inhibitors mainly focusing on central hydrophobic core Aβ16-20 (KLVFF) have been reported in recent years. Herein, we report pentapeptides -, based on the β-turn-inducing fragment Aβ19-23 (FFAED). The synthesis of peptides - was carried out using Fmoc/tBu-based solid-phase peptide synthesis technique, and it was found that pentapeptide potently inhibit the aggregation propensity of Aβ42, when incubated with it at 37 °C for 48 h. The aggregation inhibition study was conducted using thioflavin T-based …

Nifuroxazide And 4-Hydroxybenzhydrazone Derivatives As New Antiparasitic (Trypanosoma Cruzi And Leishmania Mexicana) And Anti-Mycobacterium Tuberculosis Agents, Timoteo Delgado-Maldonado, Diana V. Navarrete-Carriola, Lenci K. Vazquez-Jimenez, Alma D. Paz-Gonzalez, Baojie Wan, Scott Franzblau, Othman Mueen Mohammed, Lorena Rodríguez-Páez, Charmina Aguirre-Alvarado, Debasish Bandyopadhyay

School of Integrative Biological & Chemical Sciences Faculty Publications

Background/Objectives: Nifuroxazide (Nfz) is a drug that has been used as a scaffold for designing antimicrobial and antiparasitic agents. This study aimed to synthesize and evaluate in vitro of Nfz and twenty-five 4-hydroxybenzhydrazone derivatives as potential anti-Trypanosoma cruzi, anti-Leishmania mexicana, and anti-Mycobacterium tuberculosis agents.

Methods: The compounds were synthesized by condensing 4-hydroxybenzhydrazide with appropriate aldehydes in acidic conditions and structurally confirmed by spectroscopic techniques. All compounds were evaluated in vitro against T. cruzi strains (NINOA and A1), L. mexicana (M379 and FCQEPS strains), and M. tuberculosis (H37Rv strain), followed by enzymatic assays against T. cruzi …

Theoretical And Experimental Synthesis Of Β-Fluorinated Morphine Derivative For Selective Binding In Inflamed Tissue, Thu Doan, Amelia Bayha, Adel Martinez, Nayiri Alexander

Student Scholar Symposium Abstracts and Posters

Over the past two decades, the United States has experienced a substantial rise in opioid overdoses and related fatalities. Morphine is a frequent prescription for pain management following traumatic procedures and contributes to potential tolerance and dependency with prolonged use. By reconstructing the structure of morphine, adverse side effects may be eliminated. Previous studies have identified several morphine derivatives that, in theory, could result in fewer side effects. This was determined by a decreased pKₐ of the biochemically active amine group to promote the selective binding in peripheral opioid receptors within inflamed tissue (pH=6-6.5). This activation provides analgesia while central …