Medicine and Health Sciences Commons^™

Synthesis Of 2,4,6-Substituted Pyrrolo[2,3-D]Pyrimidines As Potential Anticancer Agents, Si Yang

Electronic Theses and Dissertations

This thesis mainly focuses on the introduction of the background and work have been done in the areas of antifolates development, such as folate function, its three uptake mechanisms inside human cells, antifolates’ role in chemotherapy, et. al. In addition, the Structure-Activity-Relationship design rationale for the series of antifolates will also be discussed. Nevertheless, the details of synthesizing these pyrrolo[2,3-d]pyrimidines as potential antifolates have been described, including chemistry reviews on the pyrrolo[2,3-d]pyrimidine scaffold, and the challenges encountered and the solutions how to solve or improve in order to achieve better yield.

Role Of Human Arylamine N-Acetyltransferase 1 In Tumorigenesis And Cancer Biology., Marcus William Stepp

Electronic Theses and Dissertations

Human arylamine N-acetyltransferase 1 (NAT1) is a well-known phase II metabolic enzyme that has been associated with carcinogenesis. Its role in the biotransformation of aromatic and heterocyclic amine carcinogens has been investigated for many years, but more recent investigations focus on a possible endogenous role of human NAT1 in cancer initiation and progression. To further explore and understand possible endogenous roles for NAT1, we conducted in vitro enzymatic reactions, in vivo studies using homozygous high (rapid) or low (slow) NAT2 activity congenic F344.WKY rats, and genetically modified human breast cancer cell lines. Human NAT1 and rodent NAT2 hydrolyzed acetyl-coenzyme …

Withaferin A Synergistically Enhances The Effects Of Paclitaxel Against Lung Cancer., Al Hassan Kyakulaga

Electronic Theses and Dissertations

Lung cancer is the leading cause of cancer-related deaths among both men and women in the U.S and worldwide. Today, paclitaxel (PAC) or taxol alongside platinum-based drugs is the most widely used agent as the first-line regimen for advanced NSCLC. However, due to toxicity, drug resistance, solubility and efficacy issues, efficacy has plateaued. In the present study, the potential of a novel plant-derived steroidal-lactone, withaferin A (WFA), for clinical use alongside PAC to improve efficacy against NSCLC was explored. The anticancer effects of PAC and WFA alone, and in combination against the in vitro cell proliferation, cell adhesion, migration and …

Burden Of Illness And Pharmacoeconomic Evaluation Of Lumacaftor/Ivacaftor In Cystic Fibrosis, Pratyusha Vadagam

Electronic Theses and Dissertations

Objectives: (1) To estimate the burden of illness in cystic fibrosis (CF) using 2010-2014 Medical Expenditure Panel Survey (MEPS) data, and (2) to conduct a pharmacoeconomic evaluation of lumacaftor/ivacaftor in the treatment of CF.

Methods: The study was conducted in two parts. Part 1 involved a retrospective analysis using individuals in MEPS database with an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis code of 277.00 for a principal diagnosis of CF. Dependent variables were cumulative and out-of-pocket (OOP) expenditures and independent variables included patient demographics and clinical characteristics. Unweighted and weighted estimates of expenditure in CF group, …

Target Based Design And Synthesis Of Fused Pyrimidines In The Potential Treatment Of Cancer And Opportunistic Infection, Khushbu Shah

Electronic Theses and Dissertations

This dissertation describes an introduction, background and research progress in the areas of agents designed as (a) selective Pneumocystis jirovecii dihydrofolate reductase (pjDHFR) inhibitors for pneumocystis pneumonia (PCP) infection; (b) inhibitors of microtubule polymerization and multiple receptor tyrosine kinase (RTK) for potential treatment of cancer; and (c) substrates for tumor-targeted therapy for cancer.

PCP is a host species-specific infection. Most of the drugs, synthesized and evaluated so far, have been tested against Pneumocystis carinii dihydrofolate reductase (the causative organism in rats), which would not necessarily be effective against pjDHFR (the causative organism in humans). Trimethoprim-sulfamethoxazole (TMP-SMX) combination, which has been …

Synthesis, Chemistry, Biological Evaluation And Structure-Activity Relationships Of Rac- And Chiral 6-Desmethyl-5Β –Hydroxy-D-Secoartemisinin And Analogs, Mohamed Elsideiq Jihan

Electronic Theses and Dissertations

The prevention and cure of malaria is difficult as it thrives under poor socio- and pharmacoeconomic conditions in third world, tropical and subtropical regions. It is a parasitic disease spread through the bite of an infected Anopheles mosquito. In humans, malaria can be caused by several Plasmodium species that include: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae and Plasmodium knowlesi. The natural product artemisinin is a sesquiterpene lactone with an endoperoxide bridge isolated from the Chinese annual herb qinghao (Artemisia annua L or sweet wormwood). The relatively stable endoperoxide bridge is essential for their antimalarial activity. The synthesis of …

Preparation And Characterization Of Acitretin-Loaded Niosomes For Psoriasis Treatment, Marey Abdulmootani Almaghrabi

Electronic Theses and Dissertations

Psoriasis is a chronic skin disease that manifests as impaired epidermal differentiation. The disease is typically treated with acitretin, an effective oral cytotoxic agent. However, due to its side effects, its use is highly limited. Topical delivery of acitretin may decrease the systemic toxicity and increase the drug’s bioavailability at the pathological site. However, this approach has some limitations. The decrease in skin integrity due to psoriasis could lead to escape of drug into the systemic circulation system and consequently compromise the topical approach. Also, the high instability of acitretin in the presence of heat could limit its topical application. …

Predictors Of Medication Nonadherence In Children/Adolescents With Attention Deficit Hyperactivity Disorder (Adhd) In Mississippi Medicaid Program, Wahidullah Noori

Electronic Theses and Dissertations

Objectives: To examine adherence to ADHD stimulant medications and determined the condition-related, therapy-related, patient-related, health-system related, and social and economic related predictors of medication nonadherence in children/adolescents (4 – 18 years) with ADHD enrolled in Mississippi Medicaid Program. Methods: This was a retrospective cohort study of the Mississippi Medicaid administrative claims data. Data was analyzed from March 01, 2014 to February 29, 2016. Adherence was calculated as the proportion of days covered (PDC). PDC was calculated including and excluding summer break (June – August) and at two different timelines, at 6 months and 12 months depending upon the length of …

Burden Of Depression Among Individuals With Irritable Bowel Syndrome(Ibs) In The Medicaid Population, Kaustuv Bhattacharya

Electronic Theses and Dissertations

Objective: to determine the period prevalence of IBS and comorbid depression among individuals with Irritable Bowel Syndrome (IBS) in multi-state Medicaid population, and to assess the impact of comorbid depression on healthcare utilization and costs among individuals with IBS enrolled in fee-for-service Medicaid program. Methods: a retrospective cohort study was conducted using 2006-2008 Medicaid analytic extract files for 39 states. Beneficiaries with IBS were identified based on any medical claims for the disease. Beneficiaries with one or more medical claims for depression during the study period were considered to have had comorbid depression. For each beneficiary, the first claim for …

Lipid Based Frameworks And Topical Ocular Inserts For The Delivery Of Small Molecule Therapeutics To The Posterior Segment Of The Eye, Sai Prachetan Balguri

Electronic Theses and Dissertations

Lipid based systems and topical ocular inserts of various drugs were developed for the intervention/treatment of posterior segment ocular complications. Indomethacin (IN) was developed into solid lipid nanoparticles (SLNs) and Nanostructured lipid carriers (NLCs). Effect of surface functionalization using chitosan (CS) on lipid nanocarriers was tested to evaluate corneal penetration. Surface modification of SLNs with CS increased ocular penetration of IN. NLCs maintained significantly higher IN concentrations in all ocular tissues tested, compared to the other formulations evaluated in vivo. Effect of surface poly (ethylene) glycol (PEG) functionalization of the NLCs on ocular disposition was studied using Ciprofloxacin (CIP) as …

Molecular Characterization Of The Opioid Receptors: Design, Development, And Preclinical Evaluation Of Salvinorin A-Based Molecular Probes., Adam Keasling

Electronic Theses and Dissertations

The field of salvinorin chemistry represents a novel and emerging field of opioid research. The novelty is derived from the lead pharmacophore: salvinorin A — a neoclerodane diterpenoid natural product isolated from Salvia divinorum. Salvinorin A represents a pharmacologically unique compound in that it is the first known non-nitrogenous KOR subtype-selective agonist, exhibits a comparatively safe physiological profile with no reports of toxicological effects in clinical trials, and, most importantly, has a steadily growing body of literature indicating potentially useful clinical applications (e.g. antinociceptive, anti-addictive, antipruritic, neuroprotective, etc.). This has encouraged the development of analogues as essential molecular probes to …

Development Of Phenotypic Drug Discovery Models For Tropical Parasitic Diseases, Surendra Kumar Jain

Electronic Theses and Dissertations

Malaria and visceral leishmaniasis are major killer parasitic diseases. These diseases though occur primarily in tropical countries; economic burden and overall health impacts of malaria and leishmaniasis are global. The emergence of drug-resistant and more-virulent strains of the pathogens has further amplified the problems. New drug discovery approaches primarily rely on in vitro and in vivo models of the disease. The pathogens causing leishmaniasis and malaria are intracellular. Leishmania parasite grows as amastigotes in macrophages cells, and malaria parasite grows within the hepatocytes or erythrocytes. The intracellular forms of the pathogens are responsible for the pathophysiology of the diseases. New …

Patient Friendly Formulations Utilizing Hot Melt Extrusion Technology, Manjeet Bhagwan Pimparade

Electronic Theses and Dissertations

This research work exhibited the new outlook of hot melt extrusion technology for orally disintegrating tablet, fast disintegration films and fixed dose combinations. Previous research demonstrated these applications by conventional formulation techniques which has inherent shortcoming of use of large amount of solvent and batch size manufacturing. This present work addressed some of the unique challenges which could provide patients ease of administration and reduce dosing frequencies, and moreover, mitigate the manufacturing challenges. For orally disintegrating tablet study, ethylcellulose, along with a suitable plasticizer, was used as a polymeric carrier. Pore forming agents were incorporated into the extruded matrix to …

Identification Of Cdks As Novel Targets Of Aspirin And Its Metabolites: A Potential Role In Cancer Prevention, Rakesh Dachineni

Electronic Theses and Dissertations

Background:
The pursuit of drugs that inhibit cyclin-dependent kinases (CDKs) has been an intense area of research for more than 15 years. Till date, although multiple CDK inhibitors have been identified and few are undergoing clinical trials, only two synthetic drugs have been approved by Food and Drug Administration (FDA) for use in the treatment of cancer. These two drugs are mainly used for the treatment of metastatic breast cancer in combination with other drugs; however they have toxicity associated with their use and extends patients life not more than 24 months. Therefore, there is an urgent need for …

Comprehensive Structural, Thermal And Toxicological Characterization Of 1-Ethyl-3-Methylimidazolium Alkylbenzenesulfonate Ionic Liquids, Hiranmayee Kandala

Electronic Theses and Dissertations

Synthesis and characterization of 1-ethyl-3- methylimidazolium alkylbenzenesulfonate ionic liquids for extraction of lignin from prairie cord grass have been studied. The ionic liquids (ILs) 1-ethyl-3- methylimidazolium benzenesulfonate (EBS), 1-ethyl-3- methylimidazolium toluenesulfonate (ETS) and 1-ethyl-3- methylimidazolium xylenesulfonate (EXS) have been synthesized in this research. An extensive structural, physical, thermal and toxicological characterization has been performed to understand the behavior of these ionic liquids. The reaction yield for the synthesis of EBS, ETS, and EXS ionic liquids was determined to be 91.2 ± 1.5 %, 96.1 ± 0.7 %, 99.0 ± 0.5 % respectively. Spectral analysis using NMR and FTIR confirms the …

Food Protein-Based Core-Shell Nanocarriers For Oral Drug Delivery Applications: (Influence Of Shell Composition On In Vitro And In Vivo Functional Performance Of Zein Nanocarriers, Md Saiful Islam

Electronic Theses and Dissertations

Oral delivery is the most preferred route for drug administration. Oral drug delivery is limited by poor physicochemical properties of drugs and physiological barriers in the gastrointestinal tract. To this end, there is a need for developing new carrier systems to enhance the oral bioavailability of poorly absorbed molecules. Food-grade biopolymers are attractive materials for developing drug delivery carriers’ due to their unique properties and proven safety. Six different core-shell nanocarriers were prepared using food-grade biopolymers including zein-casein (ZC) nanoparticles, zein-lactoferrin (ZLF) nanoparticles, zein-β-lactoglobulin (ZLG) nanoparticles, zein-whey protein isolate (ZWP) nanoparticles, zein-pluronic-lecithin (ZPL) nanoparticles and zein-PEG (ZPEG) micelles. The study …

Phytochemical Investigation Of Psychoactive Medicinal Plants For The Treatment Of Neurological Disorders, Vedanjali Gogineni

Electronic Theses and Dissertations

Neurological disorders include disorders such as migraine, tension-type headaches, Parkinson’s disease (PD), epilepsy, dementia, and Alzheimer’s disease (AD). Globally, PD is the second most comneurodegenerative disorder following AD. In developed countries, PD affects 1% of all population over 60 years of age. The prevalence of PD is increasing over the years and is expected to double by 2030. It is proposed that combination of dopaminergic drugs with monoamine oxidase B (MAO-B) inhibitors, anticholinergics, catechol-O-methyl transferase inhibitors, and other non-dopaminergic drugs can better alleviate levodopa-induced motor complications along with better control of motor symptoms. MAO-B inhibitors play a significant role in …

Synthesis And Characterization Of Ph/Temperature Dual Sensitive Multiblock Copolymer For Drug Delivery, Hyung Kyung Lee

Electronic Theses and Dissertations

The objective of this study was to develop a novel multiblock copolymer (MBCP) with temperature/pH dual-sensitivity which undergoes gelation at body temperature and degradation at acidic pH for controlled drug delivery applications. The MBCP with molecular weight of 42000 Da was synthesized by polycondensation between an acid-labile ketal linker, 2,2-bis(aminoethoxy)propane (BAP) and Pluronic® P104 using L-lysine diisocyanate ethyl ester (LDI) or 1,6-Diisocyanatohexane (HDI). The gelation temperature of 20% (w/v) MBCP was in the range of 29 to 31 ºC when tested with three different techniques: rheometer, test tube inversion method, and falling ball method. The polymer shopH-triggered degradation and drug …