Medicine and Health Sciences Commons^™

Delineating The Impacts Of Race, Aging, And Chronic Kidney Disease On Cytochrome P450 3a And Major Drug Transporters In Thai Population Using Physiologically-Based Pharmacokinetic Model, Udomsak Udomnilobol

Chulalongkorn University Theses and Dissertations (Chula ETD)

Race, aging, and organ impairment are population intrinsic factors that affect drug pharmacokinetic (PK) possibly through changing in function and/or expression of drug metabolizing enzymes and transporters. The impacts of aging and chronic kidney disease (CKD) on CYP3A, but not drug transporters, were demonstrated in Thai population receiving a microdose cocktail containing 5 probe substrates (midazolam, dabigatran etexilate, pitavastatin, rosuvastatin, and atorvastatin). This study therefore aimed to further investigate the impacts of race, aging, and CKD on the drug transporters in Thai subjects, using the physiologically-based pharmacokinetic (PBPK) approach. The population PBPK models were newly developed specifically to 3 groups …

Notch2 Activation Of Full-Length And Truncated Recombinant Jagged1 Fused With Human Igg1 Fc Produced In Mammalian Expression System, Y Tran Nhu

Chulalongkorn University Theses and Dissertations (Chula ETD)

Osteoporosis associated with old ages has emerged in 21st century as an increasing issue. To stimulate the mineral deposition in bone cells, Jagged1 (Jag1) protein has been demonstrated to trigger mineralization via Notch signaling pathway by binding to Notch2 receptor. Therefore, the Jag1 protein is one of promising candidates for osteoporosis treatment. However, Jag1 consisting of 1218 amino acids is infeasible to apply in clinical uses. Here we engineered Jag1 into truncated proteins containing key domains, Delta–Serrate–Lag-2 domain, N-terminal C2 domain and several epidermal growth factor–like domains which could be responsible for the binding of Notch receptor. To ensure the …

Formulation And Characterization Of Oral Dissolving Films With Ascorbic Acid, Ava Atri

Selected Full-Text Master Theses 2021-

People are becoming increasingly health conscious and the popularity of dietary supplements is growing. More specifically, consumers have become focused on improving the beauty of their hair, skin and nails and improving the health of their immune systems. Vitamin C or ascorbic acid provides many health and beauty benefits. Because humans are unable to synthesize vitamin C endogenously, it is an essential dietary component that one must consume either through foods or through supplements. For beauty, ascorbic acid supports the biosynthesis of collagen which is important for maintaining skin’s elasticity as well as for wound healing. Ongoing research studies are …

Aztreonam Utilization Within Emergency Departments In A Large Community Hospital Network, Peter Yakoub Pharmd, Katie Nesbitt Pharmd, Bcps, Laura Koons Pharmd, Msp, Bcccp

Department of Pharmacy

No abstract provided.

Medication Use Evaluation Of Enoxaparin Dosing Within Maternal Health Units, Brianna Schafer Pharmd, Katelin Kimler Pharmd, Bcpps

Department of Pharmacy

No abstract provided.

Improving Pharmacovigilance Signal Detection From Clinical Notes With Locality Sensitive Neural Concept Embeddings, Justin Mower, Elmer Bernstam, Hua Xu, Sahiti Myneni, Devika Subramanian, Trevor Cohen

Faculty, Staff and Student Publications

Although pharmaceutical products undergo clinical trials to profile efficacy and safety, some adverse drug reactions (ADRs) are only discovered after release to market. Post-market drug safety surveillance - pharmacovigilance - leverages information from various sources to proactively identify such ADRs. Clinical notes are one source of observational data that could assist this process, but their inherent complexity can obfuscate possible ADR signals. In previous research, embeddings trained on observational reports have improved detection of such signals over commonly used statistical measures. Moreover, neural embedding methods which further encode juxtapositional information have shown promise on analogical retrieval tasks, suggesting proximity-based alternatives …

Equitable Pharmacogenetic Testing Implementation For Rural And Underserved Populations, Shayna Killam

Graduate Student Theses, Dissertations, & Professional Papers

Pharmacogenetic testing has potential to transform healthcare, yet implementation strategies have been limited to major academic medical centers serving metropolitan communities and large health systems. In contrast, rural, community-based health systems are slow to implement these advances, threatening to exacerbate existing healthcare disparities for rural populations. A majority of Montanans live in rural areas, with unique challenges in providing access to pharmacogenetics.

We have established partnerships with three clinical sites who serve rural, underserved populations including American Indian, pediatric, and low socioeconomic status patients. We conducted a needs assessment for pharmacogenetic testing implementation by interviewing 48 key stakeholders. Interview questions …

The Sequence Dependent Nanoscale Structure Of Cenp-A Nucleosomes, Tommy Stormberg, Yuri L. Lyubchenko

Journal Articles: Pharmaceutical Sciences

CENP-A is a histone variant found in high abundance at the centromere in humans. At the centromere, this histone variant replaces the histone H3 found throughout the bulk chromatin. Additionally, the centromere comprises tandem repeats of α-satellite DNA, which CENP-A nucleosomes assemble upon. However, the effect of the DNA sequence on the nucleosome assembly and centromere formation remains poorly understood. Here, we investigated the structure of nucleosomes assembled with the CENP-A variant using Atomic Force Microscopy. We assembled both CENP-A nucleosomes and H3 nucleosomes on a DNA substrate containing an α-satellite motif and characterized their positioning and wrapping efficiency. We …

Assessing The Accuracy And Deficits Of Popular Drug-Interaction Software Programs In Detecting Interactions Between Cannabis And Pharmaceutical Drugs, Nathan C. Ramsbacher

Undergraduate Theses, Professional Papers, and Capstone Artifacts

- Purpose – The management of drug interactions in healthcare is a large concern for pharmacists and other healthcare professionals, especially for patients requiring large amounts of medications. Healthcare professionals and patients alike utilize drug-interaction software programs (DISPs) frequently to manage medications and make clinical decisions. There is a large discrepancy between DISPs in terms of detecting clinically significant drug interactions. Notably, cannabis does not flag as an interaction as reliably as pharmaceutical drugs on many DISPs. With rising cannabis use in the United States, patients deserve to make decisions on how to safely use cannabis with their prescription drugs …

Building Tools For Improved Modulation Of The Human Gabaa Receptor, A Central Nervous System Target For The Treatment Of Anxiety, Garrett Edward Zinck

Theses and Dissertations--Pharmacy

In the U.S., anxiety is recognized as an increasing range of mentally and physically debilitating psychiatric health disorders with significant economic repercussions. Over the last 20 years, several novel anti-anxiety therapies have entered the drug development pipeline, but none have made it to market.

The work in this dissertation focused on structurally modifying valerenic acid (VA), a structurally unique carboxylated sesquiterpene acid found in Valeriana officinalis. VA is putatively reported to have allosteric modulatory activity of the human GABA_A receptor, a ligand-gated ion channel responsible for attenuating neurotransmissions. Structural modeling of VA’s GABA_A receptor interaction suggests that …

Analysis Of Potential Facilitators To Use Of Hiv Pre-Exposure Prophylaxis (Prep) In A Young Transgender Population, Noah Dixon

Theses and Dissertations--Pharmacy

Pre-exposure prophylaxis for HIV prevention (PrEP) is heavily under-utilized in transgender youth, a population which experiences high risk factors for contracting HIV and exhibits unique barriers to care. This retrospective study used a secondary data analysis of survey results from transgender youth between 16-and 24-years-old to analyze various exposures for association with PrEP use. It was hypothesized that medical gender affirming therapy, mental health care treatment, and HIV programming would be independently associated with increased use of PrEP in transgender youth. It was found that only HIV prevention services and programming related to HIV or gender identity were associated with …

Studies Toward The Development Of An Improved Countermeasure For Synthetic Opioid Overdose, Sidnee L. Hedrick

Theses and Dissertations--Pharmacy

One of the most prominent opioid analgesics in the United States is the high potency agonist fentanyl. It is used in the treatment of acute and chronic pain and as an anesthetic adjuvant. When used inappropriately, however, ingestion of just a few milligrams of fentanyl or other synthetic opioid can cause opioid-induced respiratory depression (OIRD), often leading to death. Currently, the treatment of choice for OIRD is the opioid receptor antagonist naloxone. Recent reports, however, suggest that higher doses or repeated dosing of naloxone (due to recurrence of respiratory depression) may be required to fully reverse fentanyl-induced respiratory depression, rendering …

Investigating The Physical Stability Of Amorphous Pharmaceutical Formulations, Travis W. Jarrells

Theses and Dissertations--Pharmacy

Amorphous formulations, including amorphous solid dispersions (ASDs), consisting of the active pharmaceutical ingredient (API) intimately mixed in a polymeric matrix, are an attractive formulation approach to improve drug delivery, dissolution, and solubility. However, an amorphous API in an ASD is in a higher energy state compared to the crystalline drug and results in most ASDs being inherently unstable. The polymer helps to stabilize the amorphous drug against crystallization such that the resulting homogenous mixture maintains its solubility advantage relative to the crystalline form. One challenge of ASDs is that the presence of impurities including crystals or residual solvent, variations in …

Response Of Dopaminergic System To Cocaine Exposure, Recovery After Cocaine Abstinence, And Impact Of A Long-Acting Cocaine Hydrolase, Jing Deng

Theses and Dissertations--Pharmacy

Cocaine produces its physiological effects by targeting multiple proteins in the central nervous system, particularly by binding with dopamine transporter (DAT) to block the normal dopamine (DA) recycling process. This process along with the pleasure feeling would wear off shortly after the abstinence from the drug. However, chronic cocaine use is associated with neuroadaptations in the dopaminergic system, including increases in the density of DAT on plasma membrane of dopaminergic neurons. Given the critical role of DAT in neurotransmission, various studies have been carried out on animal models to learn its structure, function, and distribution. Long-standing evidence supports that DAT …

Liposomal Technologies To Improve Gene Delivery, David Nardo Padron

Theses and Dissertations--Pharmacy

Lipid based nanoparticles (LBNs) are used in myriad applications in medicine from small molecule drug delivery to mRNA vaccines. A major contributing factor to the development of the field has been the ongoing development of novel compounds that retain the functionality of natural lipids but expand upon them through inclusion of functional moieties that can be applied to specific scientific and biomedical questions. In the body of this dissertation, an extensive overview of LBNs is provided, focusing primarily on their use in immune modulation. The research presented herein begins with the synthesis of a novel class of lipids based on …

The Relative Contribution Of Liver And Intestine In Reverse Cholesterol Transport, Rupinder Kaur

Theses and Dissertations--Pharmacy

Despite decades of advances in research, death due to cardiometabolic disease remains the largest contributor to mortality in the US. While present therapies oppose “forward cholesterol transport,” and atherosclerotic plaque progression, they do not remove cholesterol from established atherosclerotic plaques. Reverse cholesterol transport (RCT) is the active process of mobilizing peripheral cholesterol for excretion through the hepatobiliary (transhepatic cholesterol elimination, THCE) or intestinal (transintestinal cholesterol elimination, TICE) pathways. Currently, there are no clinically approved therapeutics that target RCT. Elucidation of the mechanisms that govern RCT and TICE, and the subsequent identification of novel targets is of importance. The present work …

Development Of Accurate And Efficient Computational Methodologies For Predicting Protein-Ligand And Protein-Protein Binding Free Energies, Alexander Hamilton Williams

Theses and Dissertations--Pharmacy

Computational modeling is an invaluable tool in the drug discovery process either for small ligand or protein therapeutics. The widespread availability of protein X-Ray Crystal and Cryo-Electron Microscopy (Cryo-EM) structures has allowed for more accurate molecular dynamics (MD) simulations that are not reliant on methods such as homology modeling, which may produce structures that require significant computational time to demonstrate their stability. In this thesis we describe several novel methodologies for the computationally efficient modeling of protein/ligand and protein/protein complexes that may be employed within both large-scale virtual screenings and lead compound optimization. These methodologies may also be utilized in …

Development Of Zafirlukast Derivatives Active Against Porphyromonas Gingivalis, Kaitlind C. Howard

Theses and Dissertations--Pharmacy

Periodontal diseases are inflammatory diseases that can lead to damage of the soft tissue and bone supporting the teeth. Gingivitis is the reversible early stage of gum disease, which consist of gums that bleed when brushing or flossing teeth. When left untreated, the preventable but irreversible late stage of periodontal disease, periodontitis, can lead teeth to loosen or even fall out. Oral bacterial species, such as the Gram-negative anaerobic pathogen Porphyromonas gingivalis trigger these inflammatory diseases through oral dysbiosis. P. gingivalis is a keystone pathogen, meaning that the damage caused by P. gingivalis is not proportional to its abundance. Treatment …

Polymeric Nanovaccine Delivery System For Influenza Vaccine, Chaitanya K. Valiveti

Electronic Theses and Dissertations

Vaccines are the most efficient and cost-effective method for preventing illnesses caused by infectious pathogens. Even though the great success of vaccines over decades, the development of safe and robust vaccines is still essential for emerging new pathogens, re-evolving old pathogens, and improving the insufficient protection given by existing vaccines. One of the most critical strategies for developing effective new vaccines is selecting and using a suitable adjuvant or immune stimulant. Immunologic adjuvants are essential for improving vaccine potency by enhancing the immune response of vaccine antigens. The amount of antigen could be spared with improved potency, especially during mass …

Nh125 Sensitizes Staphylococcus Aureus To Cell Wall-Targeting Antibiotics Through The Inhibition Of The Vras Sensor Histidine Kinase, Shrijan Bhattarai, Lane Marsh, Kelsey Knight, Liaqat Ali, Antonio Gomez, Allison Sunderhaus, May H. Abdelaziz

Pharmacy Faculty Publications and Presentations

Staphylococcus aureus utilizes the two-component regulatory system VraSR to receive and relay environmental stress signals, and it is implicated in the development of bacterial resistance to several antibiotics through the upregulation of cell wall synthesis. VraS inhibition was shown to extend or restore the efficacy of several clinically used antibiotics. In this work, we study the enzymatic activity of the VraS intracellular domain (GST-VraS) to determine the kinetic parameters of the ATPase reaction and characterize the inhibition of NH125 under in vitro and microbiological settings. The rate of the autophosphorylation reaction was determined at different GST-VraS concentrations (0.95 to 9.49 …

Targeting Vulnerabilities In Cell State And Calcium Signaling For The Treatment Of Lung Cancer, Clark Jones

Graduate Theses, Dissertations, and Problem Reports (ETD)

Lung cancer remains the deadliest of all cancers due to the high mutational burden associated with the disease. Combating mutational drivers and drug resistance proves to be essential in the development of novel therapies to improve patient outcomes. A first-in-class cyclic peptide known as MTI-101 has been shown to induce necrotic cell death in a caspase independent manner. MTI-101 was derived from the linear peptide known as HYD1 that was found in a high throughput screen to block cell adhesion with the extracellular matrix. The compound was further optimized and cyclized to the currently used MTI-101 that was found to …

Modulation Of Ptz-Induced Convulsions In Rats Using Topiramate Alone Or Combined With Low Dose Gamma Irradiation: Involving Akt/M-Tor Pathway, Marwa Safar

Pharmacy

The current study evaluates the anticonvulsant effect low dose whole body gamma irradiation (LDR) alone or combined with topiramate against pentylenetetrazole (PTZ)-induced convulsions. Male Wister rats received either saline or PTZ (75mg/kg i.p.). The other three groups were pretreated with single low dose radiation (0.5Gy), topiramate (50mg/kg, p.o., seven days) and TPM with LDR respectively before PTZ injection. Racine’ score, latency, and duration of the convulsions were assessed. Glutamate and GABA were measured. AKT/m-TOR signaling pathway including AKT (protein kinase B), mammalian target of rapamycin (m-TOR), protein S6, and caspase 3 were also assessed. Measurements of markers of oxidative stress …

The Combinatory Effects Of Pediatric Obesity And Ontogeny On Monocarboxylate Transporter Expression In Tissues Of Drug Disposition, Michael Ng

University of the Pacific Theses and Dissertations

Proton-coupled and sodium-dependent monocarboxylate transporters are encoded by the SLC16A and SLC5A gene family of solute carriers, and are responsible for the transport of essential nutrients such as L-lactate, pyruvate, and ketone bodies. Basigin, or CD147, acts as an ancillary protein for MCT1 and MCT4, and is involved in membrane surface expression of transporters. MCT's are also involved in the shuttling of monocarboxylic xenobiotics across cell membranes, including the drugs valproate and gamma hydroxybutyrate. MCT’s are also important for normal mammalian development, particularly during embryogenesis and early neonatal life. Previous studies have shown that ketogenic diets increase MCT expression in …

Photochemical Reaction Of Renieramycins And Evaluation Of Cytotoxicity Against Lung Cancer Cells, Suwimon Sinsook

Chulalongkorn University Theses and Dissertations (Chula ETD)

Lung cancer causes more deaths than any other type of cancers, with the majority of patients diagnosed with non-small cell lung cancer (NSCLC). Lung cancer is a difficult disease to treat because of the drug resistant problem. Therefore, there is an immediate need for effective, safe, and easily accessible anti-lung cancer drug. Ecteinascidin 743 (Trabectedin or Yondelis®), a marine-derived tetrahydroisoquinoline alkaloid, is an approved drug for treating human lung cancer. This research was studied on the semi-syntheses of new renieramycins derivatives with similar structures to above drug for discovery and development of potent NSCLC cytotoxic agents. Renieramycins was extracted from …

Anti-Inflammatory Compounds In Human Peripheral Blood Mononuclear Cells From Dendrobium Species, Virunh Kongkatitham

Chulalongkorn University Theses and Dissertations (Chula ETD)

In these studies, four new compounds including three phenanthrene derivatives (dendrocrumenols A, B and D) and one fluorenone (dendrocrumenol C) and four known compounds including gigantol, 3,7-dihydroxy-2,4,8-trimethoxyphenanthrene, densiflorol B and cypripedin were isolated from Dendrobium crumenatum Sw. Each structure of isolated compounds from D. crumenatum was elucidated by spectroscopic data. These isolated compounds were then evaluated for anti-inflammatory effects in human peripheral blood mononuclear cells (PBMCs). Among the tested compounds, dendrocrumenols B and D showed the most promising anti-inflammatory effects through inhibition of tumor necrosis factor tumor (TNF) and interleukin-2 (IL-2) in monocytes and T cells. The deep immune profiling …

Titania Nanosheets Induce Anticancer Activityin Human Non-Small Cell Lung Cancer Cells, Rapeepun Soonnarong

Chulalongkorn University Theses and Dissertations (Chula ETD)

Metal nanomaterials can enhance the efficacy of current cancer therapies. Here, we show that Ti0.8O2 nanosheets cause cytotoxicity in several lung cancer cells but not in normal cells. The nanosheet-treated cells showed certain apoptosis characteristics. Protein analysis further indicated the activation of the p53-dependent death mechanism. Transmission electron microscopy (TEM) and scanning electron microscopy (SEM) analyses revealed the cellular uptake of the nanosheets and the induction of cell morphological change. Ti0.8O2 nanosheets induce apoptosis through a molecular mechanism involving peroxynitrite (ONOO−) generation. As peroxynitrite is known to be a potent inducer of S-nitrosylation, we further found that the nanosheets mediated …

Chemical Constituents And Nitric Oxide Inhibitory Activity Of Capparis Micracantha And Maerua Siamensis, Sasiwimon Nukulkit

Chulalongkorn University Theses and Dissertations (Chula ETD)

The chemical investigation of two plants in Capparaceae family, which are Capparis micracantha and Maerua siamensis, leads to the isolation of 13 compounds. The structures of the isolates were elucidated using spectroscopy techniques and comparison of the previous reports. Of five known compounds from the stems of C. micracantha were an indole alkaloid (methyl 6-methoxy-3-indolecarbonate), a benzoic acid derivative (vanillic acid), a lignan [(−)-syringaresinol], and two stilbene dimers [(+)-ampelopsin A and (−)-pauciflorol E]. In addition, eight new indole alkaloids named (+)-maeruanitrile A, maeruanitrile B, maeroximes A-C and maeruabisindoles A-C were isolated from the roots of M. siamensis,. All isolates were …

Neuroprotective Effect Of Intranasal Delivery Of Asiatic Acid Against Amyloid Beta1-42-Induced Alzheimer's Disease In Mice, Ridho Islamie

Chulalongkorn University Theses and Dissertations (Chula ETD)

Asiatic acid (AA) is an active natural compound that can be derived from Centella asiatica extract. Several pharmacological studies were reported that AA has potential as neuroprotector in the central nervous system disorders. AA penetration in the brain was limited due to its low bioavailability. Nasal delivery system of solid lipid nanoparticles (SLNs) loaded-AA was developed to increase AA penetration in the brain. The current study aimed to investigate neuroprotective effect and protective mechanisms of AA in SLNs by nasal-to-brain delivery technique against Aβ1–42 induced memory impairment by in vivo study. Male ICR mice were divided into six groups (n=11-12/group); …

Medication Usage In Independent Living: A Continuing Care Retirement Community Aging In Place Initiative, Aarti Deshpande, Carrie B Rubenstein, Ruth Benfield, Lee Burnside

All Poster Presentations

Purpose: The purpose of the study was to identify medication use concerns in this community.

Background: In this study, Swedish Geriatric Medicine Fellow partnered with this community to identify medication use concerns in this population.

Continuing Care Retirement Communities (CCRCs) are intended to support residents as they age in place. These communities tend to be well resourced but less studied. This survey attempts to identify medication use concerns in this population. Mirabella CCRC has 324 Independent living (IL) residents, 82 of which are couples. The average age is 85 years. The current cost of an IL unit is from $4673- …

Trajectories Of Medication Non-Adherence With Time-Varying Predictors And Association With Health Outcomes: A Comparison Of Classical Statistical Methods With Machine Learning Algorithms, Vasco Pontinha

Theses and Dissertations

Background: Medication adherence is a major obstacle to improving health care outcomes in long-term therapies for chronic diseases. According to the World Health Organization, interventions for improving medication adherence can have a higher impact on the health of the population than any other advance in medical treatments. Approximately 125,000 individuals die every year in the U.S. because of non-adherence to medication, representing societal costs of $100-289 billion. Previous research has successfully used group-based trajectories methods to identify similar longitudinal medication adherence trajectories. However, medication adherence is not an isolated behavior and is influenced by many factors that current interventions fail …