Therapeutics Commons^™

Acute And Chronic Dosing Of A High-Affinity Rat/Mouse Chimeric Transferrin Receptor Antibody In Mice, Demi M. Castellanos, Jiahong Sun, Joshua Yang, Weijun Ou, Alexander C. Zambon, William M. Pardridge, Rachita K. Sumbria

Pharmacy Faculty Articles and Research

Non-invasive brain delivery of neurotherapeutics is challenging due to the blood-brain barrier. The revived interest in transferrin receptor antibodies (TfRMAbs) as brain drug-delivery vectors has revealed the effect of dosing regimen, valency, and affinity on brain uptake, TfR expression, and Fc-effector function side effects. These studies have primarily used monovalent TfRMAbs with a human constant region following acute intravenous dosing in mice. The effects of a high-affinity bivalent TfRMAb with a murine constant region, without a fusion partner, following extravascular dosing in mice are, however, not well characterized. Here we elucidate the plasma pharmacokinetics and safety of a high-affinity bivalent …

Therapeutic Potential Of A Ketogenic Diet In The Treatment Of Major Depressive Disorder, Jordan A. Murrin

Masters Theses, 2020-current

Major depressive disorder (MDD) is the second most common mental health condition and a leading cause of disability in the world. It is theorized that MDD develops from a combination of biological, psychological, and social stressors. The condition is typically treated using pharmaceuticals and psychotherapy. However, not all individuals with MDD have access to or choose to use these treatments, or may prefer to incorporate therapeutic lifestyle changes such as exercise, sleep, and healthy eating. Even with treatment, MDD can alter brain structure and function, leading to the development of comorbid mental health and chronic metabolic conditions like obesity, cardiovascular …

An Epistatic Interaction Between Pre-Natal Smoke Exposure And Socioeconomic Status Has A Significant Impact On Bronchodilator Drug Response In African American Youth With Asthma., J Magaña, M G Contreras, K L Keys, O Risse-Adams, P C Goddard, A M Zeiger, A C Y Mak, J R Elhawary, L A Samedy-Bates, E Lee, N Thakur, D Hu, C Eng, S Salazar, S Huntsman, T Hu, E G Burchard, M J White

Department of Medicine Faculty Papers

Background: Asthma is one of the leading chronic illnesses among children in the United States. Asthma prevalence is higher among African Americans (11.2%) compared to European Americans (7.7%). Bronchodilator medications are part of the first-line therapy, and the rescue medication, for acute asthma symptoms. Bronchodilator drug response (BDR) varies substantially among different racial/ethnic groups. Asthma prevalence in African Americans is only 3.5% higher than that of European Americans, however, asthma mortality among African Americans is four times that of European Americans; variation in BDR may play an important role in explaining this health disparity. To improve our understanding of disparate …

Lessons Amidst A Pandemic, Mary I. Fisher

Physical Therapy Faculty Publications

No abstract provided.

Targeting The Transferrin Receptor To Develop Erythropoietin For Alzheimer’S Disease, Rachita K. Sumbria

Pharmacy Faculty Articles and Research

"Alzheimer’s disease (AD) is the sixth leading cause of death in the United States with approximately 5.8 million Americans currently living with AD. Due to the lack of a disease modifying treatment for AD and the aging baby boomer generation, this number is projected to grow to 13.8 million by 2050 (Gaugler et al., 2019). Amyloid-beta (Aβ) plaque accumulation, one of the major pathological hallmarks of AD, can begin > 20 years before clinical symptoms of AD. By the time AD is clinically diagnosed, neuronal loss and neuropathological lesions (Aβ plaques and tau tangles) have already occurred in many brain regions …

The Partial Immersion Aquatic Approach Using Adjustable Weight Bearing To Improve Posture And Sitting Balance Adaptation For Children With Severe Cerebral Palsy, Niv Shelef

International Journal of Aquatic Research and Education

The innovative ‟Partial Immersion” Aquatic Therapy Approach was developed to enhance balance and posture during sitting adaptation for children with severe cerebral palsy who exhibit deficiency in those skills on land. Stable balance during sitting posture is one of the preconditions for hands function in activities of daily living. Aquatic skills learned during aquatic therapy were then transferred to a land environment. Therapy included the use of a treatment chair that enabled adjustable weight bearing in a series of 30 mm steps. A mixed-methods design employing a multiple case study approach (n=5) including quantitative and qualitative methods investigated the effectiveness …

Ctrp3 And Alcoholic Liver Disease In Female Mice, Callie Root

Undergraduate Honors Theses

C1q TNF Related Protein 3 (CTRP3), is a cytokine that is primarily secreted from adipose tissue, which classifies it as an adipokine. Our previous research has shown that CTRP3 prevents alcoholic fatty liver disease (ALD) in male mice. However, even when accounting for confounding factors such as absolute and relative alcohol intake, females are more sensitive to the effects of consumption compared to male mice. Therefore, the goal of this project was to determine whether CTRP3 prevented ALD in female mice. Methods: Female wild type (WT) and female CTRP3 transgenic over expressing (Tg) mice were fed an ethanol containing liquid …

Reaching The Peak, Mary I. Fisher

Physical Therapy Faculty Publications

No abstract provided.

Functional Blockade Of E-Selectin In Tumor-Associated Vessels Enhances Anti-Tumor Effect Of Doxorubicin In Breast Cancer, Yoshihiro Morita, Macall Leslie, Hiroyasu Kameyama, Ganesh L R Lokesh, Norihisa Ichimura, Rachel Davis, Natalie Hills, Nafis Hasan, Roy Zhang, Yuji Kondo, David G Gorenstein, David E Volk, Inna Chervoneva, Hallgeir Rui, Takemi Tanaka

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Chemotherapy is a mainstay of treatment for solid tumors. However, little is known about how therapy-induced immune cell infiltration may affect therapy response. We found substantial CD45+ immune cell density adjacent to E-selectin expressing inflamed vessels in doxorubicin (DOX)-treated residual human breast tumors. While CD45 level was significantly elevated in DOX-treated wildtype mice, it remained unchanged in DOX-treated tumors from E-selectin null mice. Similarly, intravenous administration of anti-E-selectin aptamer (ESTA) resulted in a significant reduction in CD45+ immune cell density in DOX-treated residual tumors, which coincided with a delay in tumor growth and lung metastasis in MMTV-pyMT mice. Additionally, both …

A Quantitative Comparison Of Arm Activity Between Women With Breast Cancer And Healthy, Mary Insana Fisher, Claire Davies, Timothy L. Uhl

Physical Therapy Faculty Publications

Purpose: Survivors of breast cancer (BC) on the non-dominant side have more persistent deficits than those with cancer on the dominant limb. What is not known is whether those with BC use their involved upper limbs more, less, or at the same level as women without BC. Accelerometer use offers a quantifiable method to measure activity levels of upper limbs. The purpose of this study was to quantify the activity levels of the non-dominant involved limb among survivors of BC and compare these values to their dominant limb, as well as the non-dominant limb of a control group.

Methods: Participants …

Validity Of The Body Scan Scanner® And Structure Sensor To Measure Limb Volume In Healthy Adults, Mary Insana Fisher, Michaela Claire Viola, Noah James Brueckner, Madison Elizabeth Wolfe, Rachel Lynn Kremer

Physical Therapy Faculty Publications

Purpose/Hypothesis: Secondary lymphedema is a chronic condition that can develop in approximately 30 percent of women treated for breast cancer. It is important to measure limb volume changes for early detection of lymphedema, when it is possible to reverse the swelling (stage 1). Common clinical measures carry concerns of infection control (water displacement), are time consuming (truncated cone calculation using circumferential measures), or expensive (perometry). Use of a portable 3D scanner addresses these concerns, but the validity is unknown. The purpose of this phase I study is to investigate the validity of the Body Scan Scanner to measure limb volume …

Comparison Of Upper Extremity Function In Women With And Women Without A History Of Breast Cancer, Mary Insana Fisher, Gilson Capilouto, Terry Malone, Heather Bush, Timothy L. Uhl

Physical Therapy Faculty Publications

Design: This was an observational cross-sectional study.

Methods: Women who were diagnosed with breast cancer and had a mean post–surgical treatment time of 51 months (range = 12–336 months) were compared with women who did not have breast cancer (CTRL group). Self-reported upper extremity function using the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire and shoulder range of motion, strength, and muscular endurance were measured. Participants were divided into 3 groups: breast cancer involving the nondominant limb (BC-ND), breast cancer involving the dominant limb (BC-DOM), and CTRL.

Results: A total of 59 women in the CTRL group, 23 …

Cancer Rehabilitation Publications (2008–2018) With A Focus On Physical Function: A Scoping Review, Shana Harrington, Nicole L. Stout, Elizabeth Hile, Mary Insana Fisher, Melissa Eden, Victoria Marchese, Lucinda Pfalzer

Physical Therapy Faculty Publications

Background: Cancer rehabilitation research has accelerated over the last decade. However, closer examination of the published literature reveals that the majority of this work has focused on psychological interventions and cognitive and behavioral therapies. Recent initiatives have aggregated expert consensus around research priorities, highlighting a dearth in research regarding measurement of and interventions for physical function. Increasingly loud calls for the need to address the myriad of physical functional impairments that develop in people living with and beyond cancer have been published in the literature. A detailed survey of the landscape of published research has not been reported to our …

You Say “Goodbye,” And I Say, “Hello, Hello, Hello.”, Mary I. Fisher

Physical Therapy Faculty Publications

No abstract provided.

Validity And Reliability Of Three-Dimensional Imaging To Measure Limb Volume: A Systematic Review, Rachel Kremer, Madison Elizabeth Wolfe, Noah James Brueckner, Michaela Claire Viola, Mary Insana Fisher

Physical Therapy Faculty Publications

Introduction: Approximately 30% of women treated for breast cancer will develop lymphedema, yet early identification can prevent this occurrence. It is important to accurately and efficiently measure limb volume to identify pre-clinical lymphedema. Three-dimensional (3 D) imaging is emerging as a potential method to meet the need for accuracy and efficiency. The purpose of this review was to evaluate the psychometrics of 3 D imaging to measure limb volume.

Methods: A systematic search of 4 databases was conducted for articles using 3 D imaging to measure limb volume. Articles were included that compared 3 D imaging to water displacement using …

Tick-Borne Infections In New Hampshire: An Evaluation Of The Diagnostic Process In A Local Patient Population, Katherine Anderson

Honors Theses and Capstones

Overall, approximately 95 percent of reported cases of vector-borne disease were associated with ticks, making these the most medically important group of arthropods in the United States.¹ Despite the prevalence of tick-borne infections, the process for the diagnosis of this condition is not well studied. This study aims to analyze data from a pool of 100 patients who underwent testing for tick-borne disease in the same institution in Dover, New Hampshire during the most recent peak tick season of 2019. Information utilized in this study included: patient age, sex, location of testing (inpatient versus outpatient), diagnostic testing methods used …

Donor Age Effects On The Proliferative And Chondrogenic/Osteogenic Differentiation Performance Of Equine Bone Marrow- And Adipose Tissue Derived Mesenchymal Stem Cells In Culture, Jasmin Bagge

Theses and Dissertations--Veterinary Science

Orthopedic injuries are a major cause of lameness and morbidity in horses. Bone marrow (BM)- and adipose tissue (AT) derived mesenchymal stem cells (MSCs) have shown potential to facilitate the repair of orthopedic injuries and are being used increasingly in veterinary clinics. Presently, the use of MSCs as a therapy for equine patients is most commonly applied as autologous transplants, using BM- and AT-MSCs harvested from the patient shortly after the time of injury. Cell-based therapies are therefore delayed to enable primary cell numbers to be expanded in culture. Of concern, however, are human and rodent studies that have shown …

The Efficacy Of Ketamine In Adult Patients With Obsessive Compulsive Disorder With Symptoms Refractory To Standard Of Care Treatment., Brooke Thornton

Capstone Showcase

First line pharmacologic treatments for adult patients with Obsessive Compulsive Disorder (OCD) involve selective serotonin/norepinephrine reuptake inhibitors (SSRI/SNRIs). These drug classes often fail to deliver timely relief of symptoms as well as maintain longevity of symptom recurrence. This research analyzed the use of ketamine in adult patients suffering with OCD for the purposes of more efficacious management of symptoms. Although ketamine demonstrated a timelier relief of symptoms in some small clinical studies, its effects were ultimately unable to be sustained long term. Additionally, a wide range of adverse effects including dissociation, and rebound symptoms were observed. As a result, large …

Theranostics For Antiretroviral Biodistribution And Pharmacokinetics, Brendan M. Ottemann

Theses & Dissertations

RATIONALE: Our laboratories birthed the field of human immunodeficiency virus (HIV) theranostics. The new field allows simultaneous detection (diagnostics) and treatment (therapeutic) for the identification, treatment and inevitable elimination of virus in cell and tissue compartments. By employing theranostics, antiretroviral drugs (ARVs) can be tracked in lymph nodes, gut, spleen and liver. Cellular viral reservoirs including CD4+ T cell populations and mononuclear phagocytes (MP; monocytes, macrophages, microglia and dendritic cells) along with subcellular endosomal structures can now be targeted for drug delivery bringing therapeutics to areas where virus replicates. The overarching idea rests in improving precision targeted ARV delivery. …

Creating An Interprofessional Collaborative Research Opportunity For Physical And Occupational Therapy Students, Anne Fleischer, Mary Insana Fisher, Shirley P. O'Brien

Physical Therapy Faculty Publications

Physical therapy (PT) and occupational therapy (OT) professional associations assert the importance that entry-level therapists learn and apply the knowledge and skills necessary for interprofessional collaborative practice; however, the majority of PT and OT programs do not have the other discipline at their university. A challenge exists for the creation of a transparent active learning opportunity promoting interprofessional student engagement when the two professions do not reside in the same university. This case study provides a model for how to feasibly create an interprofessional experience for students in universities that do not include a complementary or collaborative allied health professional …

Effects Of Dabigatran In Mouse Models Of Aging And Cerebral Amyloid Angiopathy, Neethu Michael, Mher Mahoney Grigoryan, Kelley Kilday, Rachita K. Sumbria, Vitaly Vasilevko, Joanne Van Ryn, David H. Cribbs, Annlia Paganini-Hill, Mark J. Fisher

Pharmacy Faculty Articles and Research

Oral anticoagulants are a critical component of stroke prevention, but carry a risk of brain hemorrhage. These hemorrhagic complications tend to occur in elderly individuals, especially those with predisposing conditions such as cerebral amyloid angiopathy (CAA). Clinical evidence suggests that non-vitamin K antagonist oral anticoagulants are safer than traditional oral anticoagulants. We analyzed whether the anticoagulant dabigatran produces cerebral microhemorrhage (the pathological substrate of MRI-demonstrable cerebral microbleeds) or intracerebral hemorrhage in aged mice with and without hemorrhage-predisposing angiopathy. We studied aged (22 months old) Tg2576 (a model of CAA) and wild-type (WT) littermate mice. Mice received either dabigatran etexilate (DE) …

Chemical Epitope Targeting: Review Of A Novel Screening Technology, Qurrat Ul-Ain, Rene Kandler, Dylan Gillespie, Arundhati Nag

Scholarly Undergraduate Research Journal at Clark (SURJ)

Chemical Epitope Targeting is a novel technology developed for designing peptide ligands with high affinity and specificity against specific regions of a protein that may be inaccessible to small molecules or antibodies. In this review, we summarize the key steps and significant applications of this technology. Operating on the same principles as antibody-antigen interactions, this technique involves chemically synthesizing the region of interest on the protein, called the epitope, as a polypeptide with a biotin detection tag and a strategically placed alkyne or azide presenting amino acid. The constructed epitope is screened against a comprehensive linear or cyclic One Bead …

Developing A Dissociative Nanocontainer For Peptide Drug Delivery, Michael Patrick Kelly

Dissertations, Theses, and Capstone Projects

The potency and specificity of bioactive peptides have propelled these agents to the forefront of pharmacological research. However, delivery of peptides to their molecular target in cells is a major obstacle to their widespread application. A Trojan Horse strategy of packaging a bioactive peptide within a modified protein cage to protect it during transport, and releasing it at the target site, is a promising delivery method. Recent work has demonstrated that the viral capsid of the P22 bacteriophage can be loaded with an arbitrary, genetically-encoded peptide, and externally decorated with a cell-penetrating peptide, such as HIV-Tat, to translocate across in …

The Effects Of Therapeutic Riding On Social Skills And Sensory Functioning In Children With Autism, Betsy Donahoe-Fillmore, Mary Insana Fisher, Christy Lee, Jordan Bevins, Cristin Carter, Stephanie Dailey, Kelsey Haynes, Allison Richard, Sarah Soboslay

Physical Therapy Faculty Publications

Purpose and Significance: Therapeutic riding (TR) is equine-assisted riding lessons that are adapted for people with a wide variety of impairments and is often used as an adjunct to traditional therapies. Previous research has shown that TR helped to improve sensory functioning, cognition and social skills in children with Autism Spectrum Disorder (ASD) but sessions have typically been for 10-12 weeks. The purpose of this study was to investigate if social skills and sensory functioning improved after only 8 weeks of TR.

Subjects: Children were recruited from a local TR center. Participants included seven children (5M, 2F) with a diagnosis …

The Wet Bridge Transfer System: An Novel In Vitro Tool For Assessing Exogenous Surfactant As A Pulmonary Drug Delivery Vehicle, Brandon J. Baer

Western Research Forum

Background:

Due to its complex branching structure, direct drug delivery to the remote areas of the lung is a major challenge. Consequently, most therapies, such as those treating pulmonary infection and inflammation, must utilize large systemic dosing, with the potential for adverse side effects. A novel alternative strategy is to use exogenous surfactant, a material capable of distributing throughout the lung, as a pulmonary drug delivery vehicle.

Objective:

Utilize an in vitro transferring system to assess exogenous surfactant (BLES) as a pulmonary delivery vehicle for different therapeutics.

Methods:

An in vitro technique was developed to simultaneously study surfactant delivery and …

Investigating Neuroinflammation And Demyelination In The Nervous System Of Twitcher Mice By The Use Of Immunohistochemistry, Irene Wilson

Natural Sciences and Mathematics | Biological Sciences Master's Theses

Neuroinflammation and demyelination are the hallmark lesions of the Twitcher mouse—the model of Krabbe Disease. By analyzing hemibrains and sciatic nerves via immunohistochemistry, we supported the microglial hypothesis that early activation of microglial cells, macrophages, and globoid cells in the nervous system of Twitcher mice results in specific cellular polarization states that may contribute to myelin loss. The influx of activated macrophages seen in both the central and peripheral nervous systems at days 21 and 17, respectively, accounted for this polarization. Using selected M1 and M2 markers, YKL-40, and GPNMB and CD206, respectively, we proved that microglial cells and macrophages …

Development Of A Long-Acting Nanoformulation Of Dolutegravir For Prevention And Treatment Of Hiv-1 Infection, Brady Sillman

Theses & Dissertations

Dolutegravir (DTG) is a potent human immunodeficiency virus type 1 (HIV-1) integrase strand-transfer inhibitor (INSTI) with a high barrier to viral drug resistance. However, opportunities to improve its profile abound. These include extending the drug’s apparent half-life, increasing penetrance to “putative” viral reservoirs, and reducing inherent toxicities. These highlight, in part, the need for long-acting, slow effective release antiretroviral therapy (LASER ART) delivery schemes. A long-acting (LA) DTG was made by synthesizing a hydrophobic and lipophilic prodrug encased with poloxamer (P407) surfactant. This modified DTG (MDTG) reduced systemic metabolism and polarity, increased lipophilicity and membrane permeability, improved encapsulation, and formed …

Multimodality Somatostatin Analog For Fluorescence-Guided Surgery In Cancer, Servando Hernandez Vargas

Dissertations and Theses (Open Access)

Cancer surgery remains the primary curative treatment for most solid cancers and has major therapeutic implications for patients with neuroendocrine tumors (NETs). Anatomical and functional imaging technologies are widely used during the pre- and postoperative stages, but intraoperative disease recognition relies on direct visual inspection and the hands of surgeons. The limited number of clinical tools for real-time intraoperative visual feedback restricts the ability to remove the complete cancer source and is partially responsible for the high rate of disease recurrence in patients. Intraoperative imaging with fluorescent contrast agents has the potential to improve the ability of surgeons to detect …

The Promises And Challenges Of Erythropoietin For Treatment Of Alzheimer's Disease, Jiahong Sun, Jan Michelle Martin, Victoria Vanderpoel, Rachita K. Sumbria

Pharmacy Faculty Articles and Research

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder in the world, and intracellular neurofibrillary tangles and extracellular amyloid-beta protein deposits represent the major pathological hallmarks of the disease. Currently available treatments provide some symptomatic relief but fail to modify primary pathological processes that underlie the disease. Erythropoietin (EPO), a hematopoietic growth factor, acts primarily to stimulate erythroid cell production, and is clinically used to treat anemia. EPO has evolved as a therapeutic agent for neurodegeneration and has improved neurological outcomes and AD pathology in rodents. However, penetration of the blood–brain barrier (BBB) and negative hematopoietic effects are the two …

Autologous Peripheral Nerve Grafts To The Brain For The Treatment Of Parkinson's Disease, Andrew Welleford

Theses and Dissertations--Neuroscience

Parkinson’s disease (PD) is a disorder of the nervous system that causes problems with movement (motor symptoms) as well as other problems such as mood disorders, cognitive changes, sleep disorders, constipation, pain, and other non-motor symptoms. The severity of PD symptoms worsens over time as the disease progresses, and while there are treatments for the motor and some non-motor symptoms there is no known cure for PD. Thus there is a high demand for therapies to slow the progressive neurodegeneration observed in PD. Two clinical trials at the University of Kentucky College of Medicine (NCT02369003, NCT01833364) are currently underway that …