Department: Pharmacy ![[clear]](close-x.png "Remove this limiter")
158 matches in the database.
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1.
Abdelhamid, Dalia.
Natural Products as Lead Compounds for Drug Development. Part I: Synthesis and Biological Activity of a Structurally Diverse Library of Curcumin Analogues. Part II: Synthesis of Novel Sterol Natural Products and Related Analogues as Antileishmanial Ag.
Degree: PhD, Pharmacy, 2011, Ohio State University
► Natural products have served as an effective source of drugs and drug…
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▼ Natural products have served as an effective source of drugs and drug leads throughout history. In part, this is due to the unique structures and the well-defined stereochemistry found in these compounds which allow them to interact selectively with biological target molecules. Unfortunately, most natural products themselves are not suitable for administration as drugs. Chemical synthesis, however, can be employed to study and address some of these shortcomings through manipulation of pharmacological properties, structure activity relationship studies, and the preparation of compounds for mechanistic studies by molecular biologists. In this thesis, an overview of the role of natural products is presented in order to set the stage for two current drug discovery and development studies which are based on natural product leads. The first project involves the development of a library of curcumin analogues. This effort was initially directed simply at the development of more effective anticancer agents based on the curcumin scaffold. As the project evolved, however, it became clear that a fairly comprehensive library of structurally diverse analogues may be useful for the identification of new leads which could affect other disease states or biological targets. The second project involves the isolation and development of novel compounds for the treatment of leishmaniasis, a parasitic disease. In this case, a short synthetic route was developed to give access to the scaffold of the natural products isolated from a Mexican plant. Based on this strategy, a number of analogues have been produced which have helped to define the structure-activity relationship of this class of molecules.
Advisors/Committee Members: Pui-Kai, Li.
Subjects: Chemistry; Pharmacy Sciences
Keywords: Anicancer, Curcumin, Sterol, Antileishmanial
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3.
Ahn, Sunjoo.
Novel Antimitotic Compounds with Potent In Vitro and In Vivo Antitumor Effects: the Use of Pharmacokinetics, Metabolism, Efficacy, and Toxicity Studies.
Degree: PhD, Pharmacy, 2010, Ohio State University
► We identified novel indole derivatives inhibiting human cancer cell growth with nanomolar…
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▼ We identified novel indole derivatives inhibiting human cancer cell growth with nanomolar IC50 values. Thus, we studied the mechanism of anticancer effects, pharmacokinetics, in vitro hepatic metabolism, in vivo efficacy, and/or toxicity of lead compounds I-13 and I-19. They induced a down-regulation and/or an inactivation by hyper-phosphorylation of Bcl-2. They arrested cells in the G2M phase and inhibited tubulin polymerization by binding to the colchicine-binding site. The pharmacokinetics of the lead compound, I-19, in ICR mice was determined after i.v., i.p., and p.o. administrations. I-19 was slowly cleared and highly distributed in mice. I.p. administration of I-19 was absorbed quickly with 65-94% bioavailability. In the in vitro metabolic stability study using mouse, rat, dog, monkey, and human liver microsomes, I-19 was metabolized mainly via phase I pathway and the metabolite with a reduced ketone was the predominant form by human liver microsomes. In the PC-3 xenograft models, I-13 (10 mg/kg, q2d, i.p.) and I-19 (10 mg/kg, q2w, i.p.) inhibited 58% and 68% tumor growth, respectively. Furthermore, since multidrug resistant (MDR) cell lines that over-expressed ATP-binding cassette (ABC) transporters such as P-glycoprotein were not resistant to indole compounds, in vivo efficacy of I-19 was examined in xenografts using MES-SA/DX5 cells over-expressing P-glycoprotein. I-19 (10 mg/kg, q2d, i.p.) was effective with 76% tumor growth inhibition in xenograft models using MES-SA or MES-SA/DX5 cells. In vitro studies of NGF-dependent neurite outgrowth in PC12 cells and in vivo studies of mouse behavior showed that I-19 was less neurotoxic than vinblastine and vincristine, tubulin destabilizers with known neurotoxicity. In conclusion, indole compounds inhibit tubulin polymerization via the colchicine binding site and circumvent P-glycoprotein-mediated MDR, suggesting that they may be new antimitotic agents for the treatment of patients with drug resistant cancer.
Advisors/Committee Members: Dalton, James.
Subjects: Pharmaceuticals
Keywords: drug; discovery; tubulin; indole; P-glycoprotein; prostate cancer
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4.
Aimiuwu, Josephine Eki.
Modulation of Pharmacologic Effects of 5-Azacytidine by Ribonucleotide Reductase Antisense GTI-2040.
Degree: PhD, Pharmacy, 2011, Ohio State University
► Cancer, like most human diseases is complex and the therapeutic approaches available…
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▼ Cancer, like most human diseases is complex and the therapeutic approaches available to treat this disease have limited efficacy. Therefore, combination studies of two or more anticancer drugs is expected to be essential in achieving a better therapeutic response in patients and may also provide a cure for drug-resistant cancers. Leukemia is a cancer of the blood, which results from an uncontrolled proliferation of white blood cells, thereby inhibiting its functions. Important insights into the pathogenesis of this disease have led to the development of a number of anti-leukemia drugs, including nucleoside analogs and new antisense compounds, that intervene at the level of disease progression. 5-Azacytidine and decitabine are hypomethylating agents recently approved by the U.S Food and Drug Administration for the treatment of Myelodysplastic Syndrome (MDS) and are also in clinical trials for the treatment of hematological malignancies, such as acute myeloid leukemia (AML). These drugs are approved based on their ability to induce DNA demethylation, resulting in reactivation of hypermethylation-associated silencing of tumor suppressor genes. Aracytidine (Ara-C) is another nucleoside drug, widely used as antimetabolite for the treatment of acute myelogenous leukemia. Antisense GTI-2040 is a 20-mer oligonucleotide inhibiting the expression of ribonucleotide reductase subunit M2 (RRM2) mRNA, an enzyme that has been found to be over-expressed in most cancers. In this dissertation, investigations on pharmacodynamic studies of nucleoside analogs in combination with GTI-2040 were carried out. It has been demonstrated that inhibition of cellular RR, which subsequently decreases deoxyribonucleotide triphosphate (dNTP) pools, could enhance the anti-tumor activity of subsequently administered nucleoside analogs. We have in our studies, provided both in vitro and in vivo evidences to support the novel combination treatment of antisense GTI-2040 and 5-azaC, leading to a synergistic effect. In addition, GTI-2040 decreases RRM2 levels, and most notably, we discovered that 5-azaC modulates RRM2 for the first time and this result makes RR a novel target for 5-azaC. In addition, the biomarkers involved in the development of 5-azaC and decitabine (DAC) resistances were assessed in order to elucidate the potential mechanisms that contribute to the induction of resistance in cancer cells. In a phase II evaluation of GTI-2040 in combination with Ara-C in patients with AML at The James Cancer Hospital and Research Institute at The Ohio State University, clinical pharmacokinetic of GTI-2040 and the in vitro-in vivo pharmacodynamic analysis with Ara-C was established to assist in the exploration of their pharmacokinetic-pharmacodynamic (PK-PD) correlations in relation to clinical response. Finally, our studies of GTI-2040, 5-AzaC, DAC and Ara-C provide valuable insights into their clinical development as a single agent or in combination with other drugs.
Advisors/Committee Members: Chan, Kenneth.
Subjects: Pharmaceuticals
Keywords: preclinical, clinical pharmacokinetics/pharmacodynamics, and drug development
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5.
Bahar, Mark.
Protoberberine-type Alkaloids as Lead Compounds for the Treatment of African Sleeping Sickness, Leishmaniasis, and Malaria.
Degree: PhD, Pharmacy, 2012, Ohio State University
► Natural products have played traditionally a pivotal role in the field of…
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▼ Natural products have played traditionally a pivotal role in the field of drug discovery. The impact of natural products in the biomedical sciences can be shown by a few distinct examples: The discovery of receptor sites (as in the case of nicotinic, muscarinic, and opioid receptors), the isolation of compounds with a unique activity for a disease for which there was no practical treatment (such as quinine in malaria and penicillin for bacterial infections), the identification of a novel mechanism of action in a known disease (such as the tubulin-stabilizing effect of paclitaxel in cancer), and the provision of lead molecules that can be further optimized (such as mefloquine, based on the lead compound quinine). The importance of natural products is also reflected when it is considered that over 30% of all the new small-molecule drugs approved for clinical use in Western countries and Japan during the twenty-five year period from 1981 to 2006 were either natural products or their derivatives, or synthesized molecules based on natural product pharmacophores. In the present study, a library of 128 plants available at the College of Pharmacy, The Ohio State University, was screened for antileishmanial and antitrypanosomal activities, following a standardized solvent extraction scheme (Wall et al., 1996). Among the active extracts, the entire plant of Thalictrum lucidum L. (Ranunculaceae) was selected as a potential lead and was extracted in a larger scale, with a bioactivity-guided fractionation procedure employed to identify the active principle or principles. Bioactivity studies led to the identification of berberine (85) as the main active principle of T. lucidum, with two other protoberberine-type alkaloids, jatrorrhizine (87) and palmatine (89) isolated. Following this lead, a small library of semisynthetic berberine derivatives was screened for antileishmanial and antitrypanosomal activities. Among the compounds evaluated in the in vitro test systems, samples that were labeled as 8,8-diethyldihydroberberine (HI salt) and 8,8-dimethyldihydroberberine (HI salt) were active against Leishmania donovani parasites with IC50 values of 12 and 15 ng/mL, respectively. However, both samples proved to be mixtures in NMR spectroscopic and chromatographic studies, possibly due to oxidation during prolonged storage. In an effort to identify the active principle, a semisynthetic study was carried out. Accordingly, the berberine analogue, 5,6-didehydro-8,8-diethyl-13-oxodihydroberberine chloride (129) was synthesized in sufficient amounts for further biological testing. 5,6-Didehydro-8,8-diethyl-13-oxodihydroberberine chloride s howed nanomolar level potency against the in vitro models of leishmaniasis, malaria, and trypanosomiasis used as well as activity in an in vivo model of visceral leishmaniasis. Therefore, this compound was elucidated as a bioactive oxidized form of the original 8,8-diethyldihydroberberine sample. Overall, this study describes the discovery of a berberine analogue through a semisynthetic approach with an approximately thousand-fold improvement in activity against leishmaniasis, malaria, and trypanosomiasis as compared to the parent compound. Since the starting material, berberine, is relatively inexpensive, the discovery of 8,8,-dialkyldihydroberberine derivatives may lead to a new class of affordable drugs in the field of protozoal diseases.
Advisors/Committee Members: Kinghorn, A. Douglas.
Subjects: Biomedical Research; Chemistry; Pharmacy Sciences
Keywords: leishmaniasis, trypanosomiasis, malaria, berberine, natural products, alkaloids
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6.
Baliga, Reshma S.
Roles and mechanisms of oxidant stress in cardiovascular disease.
Degree: PhD, Pharmacy, 2004, Ohio State University
► My primary dissertation focus is understanding the pathology behind cardiovascular disease across…
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▼ My primary dissertation focus is understanding the pathology behind cardiovascular disease across disease states, in an attempt to provide novel mechanistic insight so that specialized therapy can be developed. Section I: HIV related cardiovascular disease: The first four chapters: HIV-related cardiovascular complications represent increasingly important contributors to the overall morbidity and mortality of HIV/AIDS patients. Chapter 2 reviews the emergent field of HIV related vascular abnormalities primarily related to alterations in the vascular endothelium. In Chapter 3, we employed a well-established murine model of retroviral infection (LPBM5 virus) and defined the time-dependencies of retroviral progression and cardiac dysfunction corroborated our findings in human tissues. In chapter 4 we tested the hypothesis that HIV-PI’s impose direct detrimental effects on vascular endothelium. Chapter 5 details a role for direct endothelial toxicity induced by Saquinavir (SAQ). Section II deals with cardiovascular complications of diabetes in a mouse model of streptozotocin induced hyperglycemia, a type I diabetes model, studied longitudinally at 0, 1week and 5 weeks post-STZ, for assessment of diastolic and systolic performance by non-invasive echocardiography, and electrocardiographically for conduction abnormalities. We found the STZ mouse model to be appropriate for mechanistic study of Type I diabetic cardiomyopathy, providing time-dependent, clinically relevant assessments of cardiac performance (systolic, diastolic and electrocardiographic) as a foundation for further mechanistic studies, which are shown in chapter 7. Section 3, Chapter 8, appendix A and B: we looked at mechanisms of cardiac dysregulation and development of arrhythmias in canine models. In Appendix A we tested the hypothesis that two models had differing underlying mechanisms of structural remodeling, resulting in development of substrate for AF. Chapter 8, looks in more detail at the MR Dog model, studying development of AF susceptibility over time, to isolate the mechanisms of dysfunction. Finally in Appendix B we tested a novel therapeutic agent, ALT-711 that specifically targets fibrosis stability for its therapeutic value in chronic atrial dilatation (MR) induced AF. Taken together, these studies show that increased oxidative stress is a common factor in cardiovascular dysfunction across disease states, and therapeutic agents targeting oxidative damage might have unique importance to cardiovascular health.
Advisors/Committee Members: Bauer, John A.
Keywords: HIV/AIDS; atrial; endothelial; diabetic; HIV-PI; cardiac; Fibrosis
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7.
Barnett, Derek W.
PART 1. SYNTHESIS OF STABLE-ISOTOPE LABELED AMINO ACIDS PART 2. SYNTHESIS OF MECHANISTIC PROBES OF RETINOID ACTION.
Degree: PhD, Pharmacy, 2002, Ohio State University
► Stable-isotope labeled amino acids are used in nuclear magnetic resonance (NMR) spectroscopy…
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▼ Stable-isotope labeled amino acids are used in nuclear magnetic resonance (NMR) spectroscopy to facilitate protein structure determination with the use of isotope edited or filtered experiments. We are currently developing synthetic routes to 15N containing amino acids that have been stereoselectively deuterated at the beta-carbon. Once incorporated into a protein of interest, these molecules can be used to obtain stereospecific assignments of the prochiral beta-methylene protons. These assignments greatly increase the precision of the structure determination process and are critical to accurately establishing the orientation of amino acid side-chains within the protein. The utility of this strategy has been demonstrated by the synthesis of the (2S, 3R)-[3-2H,15N]-phenylalanine and (2S, 3S)-[3-2H,15N]-tyrosine derivatives. The key step in the syntheses is the alkylation of a chiral lithium enolate derived from 15N-(-)-8-phenylmenthylhippurate with an enantiotopically deuterated benzylic electrophile. A prominent feature of this strategy is its versatility. By selecting the appropriate protecting groups and electrophile, any of the four possible diastereomers can be synthesized. In addition, the method is amenable to the incorporation of various isotope labeling patterns owing to the commercial availability of different isotopomers of glycine. The details of the phenylalanine and tyrosine syntheses are presented as well as a summary of the efforts to optimize the strategy and extend the methodology to the production of several other labeled beta-methylene unit containing amino acids. N-(4-Hydroxyphenyl)retinamide (4-HPR) is a synthetic amide analog of retinoic acid that has been studied extensively as a cancer chemopreventive and chemotherapeutic agent. However, the mechanism through which 4-HPR exerts its antiproliferative effects remains unclear. It has been demonstrated that 4-HPR induces apoptosis in many tumor cell lines despite having virtually no affinity to the nuclear retinoid receptors. This is in direct contrast to retinoic acid, which possesses very high affinity for the retinoic acid receptors and induces differentiation in tumor cell lines. This data suggests that 4-HPR and retinoic acid may act at different cellular targets. In an effort to identify possible targets of 4-HPR binding, we have synthesized a series of electrophilic and photo affinity label analogs of 4-HPR. The details of the syntheses and preliminary chemical reactivity are presented.
Advisors/Committee Members: Curley Jr., Robert W.
Keywords: amino acids; stable-isotope labeling; nuclear magnetic resonance spectroscopy (NMR spectroscopy); chlorination; affinity labeling; retinoid
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8.
Bellebaum, Katherine Louise.
The Relationship Between Nurses' Work Hours, Fatigue, and Occurrence of Medication Administration Errors.
Degree: PhD, Pharmacy, 2008, Ohio State University
► Nurses are responsible for the safety of their patients. Nursing factors such…
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▼ Nurses are responsible for the safety of their patients. Nursing factors such as long work hours and fatigue are concerns as they may affect patient safety. One area of patient safety to consider is medication use, specifically medication administration errors. Quantitative data in the form of observational studies are needed to assess the impact of nurses' work hours and fatigue on medication administration errors. This non-blinded, observation-based study took place at an academic medical center in Columbus, OH. The medication administration process was observed in volunteer nurses at three points in time over a single 12-hour shift: 0-2 hours (7am-9am), 6-8 hours (1pm-3pm), and 10-12 hours (5pm-7pm). In addition to the data collected through observation, each nurse completed three questionnaires: demographic and work-related, acute fatigue, and chronic fatigue. A pilot study was conducted in both the ED and medical intensive care unit (MICU) in order to decide which setting was more feasible for this study design. Eligible nurses for the study worked in either the MICU or ED (depending on pilot results), were registered nurses, and did not work straight night shifts. Using SPSS 16.0, linear regression, repeated measures ANOVA, and frequencies were used to analyze the medication administration and nursing data. A total of 548 medication administrations were observed among the 30 MICU nurses who volunteered for this study. Within order-based errors, dose errors were the most common (6%). Administration technique errors (10.7%) were the most common within the preparation/administration-based errors, followed by administration time errors (5.7%). Within errors of process variation, not checking the patient's armband (79.6%), not double checking the MAR (16.6%), and not washing hands (12.5%) were the most common. Error rates for administration time, not washing hands, not checking armbands, and pre-charting differed significantly across the three time periods of observation. Error rates per nurse were the following: 1.5% order-based, 5.6% preparation/administration-based, and 15.9% process variation. No significant relationship existed between either work hours or fatigue and occurrence of medication administration errors. Overall, the findings of this observation-based study indicate a need for improvement in some aspects of medication administration.
Advisors/Committee Members: Pedersen, Craig.
Subjects: Nursing; Pharmaceuticals
Keywords: medication safety, medication errors, nurse fatigue
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9.
Beyer, Andrew P.
The Development and Validation of the Insomnia Treatment Satisfaction Questionnaire (ITSAT-Q).
Degree: PhD, Pharmacy, 2009, Ohio State University
► Insomnia is a condition that affects over a third of people in…
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▼ Insomnia is a condition that affects over a third of people in the United States at one point or another. While some experience insomnia symptoms for a short period of time, there are many who suffer from the effects of insomnia on a daily basis. To alleviate their symptoms, insomnia sufferers seek a variety of solutions, including pharmacological and non-pharmacological treatments. Individuals suffering from insomnia often try a number of pharmacological treatments including supplements, over-the-counter drugs, and prescription medications in an attempt to curtail their symptoms. Treatment satisfaction is a patient’s evaluation of the process of taking a medication and the outcomes associated with the medication. The purpose of this study was to develop and validate a treatment satisfaction instrument for insomnia medication. Possible items were gleaned from literature review, a panel of clinicians, and focus groups. The items were administered to a sample of 298 participants who judged the importance of each of the statements with regard to treatment satisfaction. Factor analysis and structural equation modeling were used to identify the dimensions that underlie treatments satisfaction and to refine the items to a valid and parsimonious instrument. Exploratory factor analysis revealed that five dimensions were present in the items: expectations, convenience, effectiveness, value, and a general dimension of treatment satisfaction. Confirmatory factor analysis substantiated the prior dimensions identified and demonstrated that the proposed model exhibited good fit to the data. Structural equation modeling allowed for an understanding of the relationships between the latent variables in the model and confirmed the multidimensional nature of treatment satisfaction. Findings from this study provide additional insight regarding patient perceptions of treatment satisfaction and other related therapeutic dimensions to help to optimize pharmacotherapy.
Advisors/Committee Members: Szeinbach, Sheryl.
Subjects: Health; Pharmaceuticals
Keywords: insomnia; treatment satisfaction; value; instrument development; factor analysis; structural equation modeling
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10.
Bhasin, Deepak.
Small Molecule Inhibitors asAnticancer Agents.
Degree: PhD, Pharmacy, 2011, Ohio State University
► Signal transducer and activator of transcription 3 (STAT3) is one of the…
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▼ Signal transducer and activator of transcription 3 (STAT3) is one of the downstream signaling proteins for cytokine and growth factor receptors. Receptor activation induces tyrosine phosphorylation leading to dimerization of two STAT monomers by reciprocal phosphotyrosine-SH2 interactions. This dimer translocates into the nucleus where it controls the transcription of several apoptosis and cell cycle-regulatory proteins. STAT3 has been identified to be overexpressed in many different kinds of blood malignancies and solid tumors. Inhibition of STAT3 dimerization stops translocation into the nucleus and induces apoptosis. Several novel small molecules have been synthesized using a structural-based strategy with an aim to specifically inhibit STAT3 dimerization and have been examined for their antiproliferative activity on breast, pancreatic, prostrate and brain cancer. Among the compounds synthesized, LLL-3, LLL-6 and LLL-12 were found to be active against various cancer cell lines. LLL-12 was found to be the most potent analogue among the LLL series of compounds and even more potent than known inhibitors against various cancer cells overexpressing STAT3, and it did not inhibit STAT1. LLL-12 was also found to reduce tumor growth. Arginine methylation is an important post-translational modification which mainly occurs in nuclear proteins and is involved in structural remodeling of chromatin, signal transduction, cellular proliferation, gene transcription, translation, DNA repair, apoptosis, RNA processing, and mRNA splicing. PRMT5 has been shown to catalyze the formation of monomethylargininie (MMA) and symmetric dimethylarginine (sDMA) on a variety of substrates including myelin basic protein (MBP), the Sm ribonucleoproteins, and additional proteins that require symmetric dimethylarginine residues. PRMT5 has been shown to methylate histones H2A, H3 and H4. PRMT5 has been reported to be associated with tumors. PRMT5 overexpression has been documented in multiple non-Hodgkin’s lymphoma cell lines and primary mantle cell lymphoma tumor samples. Molecular docking was used to screen a library of 10,000 compounds to identify 8 potential compounds for biological screening. Subsequent screening identified BLL-1 as our lead compound which was further modified using traditional medicinal chemistry approaches and molecular modeling. BLL-1 was the most potent compound tested on JeKo and Mino cells. Survivin is a 142 amino acid and is the smallest member of the IAP family. Survivin indirectly acts on caspases by associating with cdk4 resulting in release of p21Cip1/Waf1, which interacts with procaspase-3 to suppress Fas mediated cell death.163 Survivin also provides cytoprotection to cells against caspase-independent cell death by inhibiting the AIF pathway. Survivin is present on the mitotic machinery of dividing cells and regulates cell division. Survivin has been shown to be overexpressed in cancer. Lack of Survivin or disruption of the Survivin function would be expected to cause apoptosis in tumor cells. Structural study of compound 2 showed that its binding site is located at the dimerization interface. Compound 2 was modified with an aim to target the Survivin binding site. LLP-3 was found to be active at 50 μm against various cancer cell lines. LLP-3 also delayed mitosis and cells appeared to lose viability after being exposed to LLP-3 for 48 hours.
Advisors/Committee Members: Li, Pui-Kai.
Subjects: Chemistry; Pharmacy Sciences
Keywords: STAT3, PRMT5, Survivin inhibitors
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11.
Bhosle, Monali Jaysing.
Outcomes associated with adjuvant hormonal therapy: are they any differences between black and white women with primary breast cancer?.
Degree: PhD, Pharmacy, 2007, Ohio State University
► Studies have documented that racial disparities exist in breast cancer treatment and…
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▼ Studies have documented that racial disparities exist in breast cancer treatment and delivery in the United States. Medication adherence and persistence to adjuvant hormonal therapies in women with hormone receptor positive breast cancer could be important for optimum benefits and to avoid recurrences. Medication use behavior is associated with improved treatment outcomes and results in lower utilization of medical resources and costs. The objective of this study was to examine the racial differences in medication use behavior and associated healthcare costs and utilization. The conceptual model incorporated modified version of Health Belief Model and Aday-Andersen model for healthcare utilization. This was a retrospective cohort study of Medicaid enrollees with hormone receptor positive breast cancer newly starting adjuvant hormonal therapy. The study used North Carolina Medicaid data, which was linked to the North Carolina Cancer Registry. The patients were followed for one year after commencing the index medication (tamoxifen or aromatase inhibitor) to collect the data on medication utilization, healthcare costs, hospitalization and emergency department (ED) visits. Demographic, clinical and medication related information was extracted from the linked data. Propensity score (PS) matching technique was used to match white and black patients on their background characteristics. A total of 206 pair matched sample cohort was used for the final analyses. Adherence levels of this study cohort were significantly lower than the generally accepted level of eighty percent. Black patients were associated with slightly decreased medication adherence as compared to white patients after controlling the type of index therapy. Annual health care costs did not differ significantly between the racial groups. Whites had a higher likelihood of hospitalizations as compared with black patients. The likelihood of ED visits did not differ significantly across the racial groups. Higher medication adherence was associated decreased likelihood of ED visit in this cohort. Disparities in medication adherence warrant raising awareness of the health care gap among broad sectors, including health care providers, patients, payors, health plan purchasers, and society at large. Multidisciplinary action which entails collaboration of healthcare professionals aiming to improve medication use behavior in black patients may prove to be an important strategy.
Advisors/Committee Members: Balkrishnan, Rajesh.
Subjects: Health Sciences, Pharmacy
Keywords: Breast Cancer, Adjuvant hormonal therapy, Medication use behavior
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12.
Bohl, Casey Edward.
Structural characterization of androgen receptor interactions with nonsteroidal ligands.
Degree: PhD, Pharmacy, 2005, Ohio State University
► The following research was aimed at uncovering the binding interactions of nonsteroidal…
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▼ The following research was aimed at uncovering the binding interactions of nonsteroidal ligands with the androgen receptor (AR). Steroidal binding to the AR is well understood through x-ray crystallography and mutational analysis. The binding mechanism for the nonsteroidal antiandrogens used in prostate cancer treatment however was unknown despite prevalent clinical use for nearly 20 years. Our laboratory discovered selective androgen receptor modulators (SARMs) by structural modification of currently available nonsteroidal antiandrogens. Collaboration with a group of medicinal chemists led to a vast number of potential therapeutic agents that target the AR, but their binding mechanism could not be explained based on currently published crystal structures complexed to steroids. We investigated the interactions between nonsteroidal ligands and the AR using a variety of approaches including molecular modeling, mutational analysis, and x-ray crystallography. Nonsteroidal ligands induced structural changes in the AR binding pocket allowing for their accommodation. Furthermore, crystal structures of currently prescribed antiandrogens complexed to mutant AR associated with resistance provided information regarding their mechanism of action. Knowledge of AR interactions with nonsteroidal ligands will provide the basis for development of improved drugs that target the AR.
Advisors/Committee Members: Dalton, James T.
Subjects: Health Sciences, Pharmacology
Keywords: bicalutamide; LBD; AR LBD; AR; SARMs; DHT; LIGANDS
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13.
Byun, Youngjoo.
Thymidine kinase as a molecular target for the development of novel anticancer and antibiotic agents.
Degree: PhD, Pharmacy, 2006, Ohio State University
► Thymidine kinase (TK), a key enzyme of the salvage pathway for DNA…
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▼ Thymidine kinase (TK), a key enzyme of the salvage pathway for DNA biosynthesis, is an attractive molecular target for the treatment of brain tumors and anthrax infections because of its high activity in tumor cells and its occurrence in pathogenic Bacillus anthracis. In tumor-related research, boron neutron capture therapy (BNCT) was chosen as the therapeutic modality. Previous structure-activity relationship (SAR) studies of 3-carboranyl thymidine analogues (3CTAs) identified one promising boron-delivery agent for BNCT, designated N5-2OH. Two feasible synthetic routes for the preparation of 10B-enriched N5-2OH were developed, which was evaluated as a boron-delivery agent for BNCT in pilot neutron irradiation experiments. Stereochemical- and geometrical N5-2OH isomers were synthesized and their substrate specificities for human thymidine kinase 1 (hTK1) were evaluated to complete SAR studies of the N5-2OH series. A computational model for the binding of the N5-2OH series to the active site of hTK1 was also developed. In order to improve physicochemical properties of 3CTAs, zwitterionic nido 3CTAs were synthesized and evaluated as boron-delivery agents for BNCT. One of these agents showed similar in vitro and in vivo biological activities as N5-2OH combined with superior physicochemical properties. The zwitterionic nido m-carborane system was further investigated. This novel type of boron cluster exhibited unique chemical features by reacting with the carbonyl group of ketones or aldehydes to afford zwitterionic iminum-substituted carboranes. In anthrax-related research, a compound library composed of 30 known antiviral and anticancer drugs was screened in phosphoryl transfer assays with B. anthracis TK and in growth inhibition studies with B. anthracis Sterne. Novel potential inhibitors of B. anthracis TK and of B. anthracis thymidine monophosphate kinase for the treatment of anthrax infections were designed as mimicks of thymidine triphosphate, the endogenous feedback inhibitor of B. anthracis TK. Twenty inhibitors were synthesized and evaluated biologically. Some of the inhibitors exhibited low IC50 values in growth inhibition studies with B. anthracis Sterne. Overall, the concept of novel antibiotics targeting B. anthracis TK was validated and two inhibitors were selected as lead compounds for further structural optimization.
Advisors/Committee Members: Tjarks, Werver.
Keywords: Thymidine kinase; Boron neutron capture therapy; N5-2OH; 3CTAs; Bacillus anthracis
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14.
Candrilli, Sean David.
Medication Adherence and Associated Outcomes in Medicaid Enrollees with Sickle Cell Disease.
Degree: PhD, Pharmacy, 2009, Ohio State University
► Background and Objective: Sickle cell disease (SCD) is an inherited disorder characterized…
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▼ Background and Objective: Sickle cell disease (SCD) is an inherited disorder characterized by the production of defective hemoglobin, which in turn leads to the formation of sickle-shaped red blood cells (RBCs). Predominantly affecting people of African descent, it is estimated that between 50,000 and 100,000 people in the United States (US) are afflicted with the disease, with approximately 2,000 new cases arising each. Patients with SCD frequently experience unexpected, intermittent, and sometimes life-threatening complications leading to increased numbers of emergency room visits and frequent hospitalizations, each with substantial economic costs. In the US alone, SCD-related inpatient costs alone are estimated to be between $500 million and $1 billion annually. Hydroxyurea (HU) is the only pharmacologic intervention approved for the treatment of HU. There is a paucity of data on of the use of HU in real-world settings among SCD populations. Further, little research exists on the extent, and implications, of HU nonadherence among SCD patients. The aim of this study was to assess the association between HU adherence and outcomes in a Medicaid-enrolled SCD population. Methods: Retrospective claims of enrollees in the North Carolina Medicaid program (6/1999 – 8/2008) were analyzed. Inclusion criteria were: ≥1 encounter with a diagnosis for SCD, ≥2 HU prescriptions; and continuous health plan enrollment for ≥12 months prior to and following HU initiation (index). Adherence was measured using the medication possession ratio (MPR), defined as the sum of HU days supplied during the 12 months following initiation divided by the number of days (365) in the follow-up period, less the number of days hospitalized. Patients with an MPR ≥0.8 were classified as adherent. Multivariate regression analyses were used to estimate the effect HU adherence on economic and clinical outcomes (e.g., costs, likelihood of event). Covariates included age, gender, race, Charlson Comorbidity Index score, and the number of SCD-related office visits in the year prior to HU initiation. Results: Three hundred and twelve subjects (51% male, 83% Black, mean age 21 years) met all inclusion criteria. Mean MPR was 0.60, and only 35% of subjects were adherent. Multivariate regression models suggest that HU adherence is significantly associated with a reduction in both all-cause and SCD-related inpatient and emergency room costs, as well as SCD-related total costs; adherence was also associated with an increase in HU and, interestingly, all-cause office visit costs. Finally, adherence was associated with a reduction in the likelihood of having an ER visit or inpatient stay, regardless of the primary reason for the encounter, as well as the likelihood of having a vaso-occlusive event. Conclusions: Adherence to HU in the analyzed SCD population is low. These data suggest, though, that increasing adherence may be associated with improved outcomes, both clinical and economic.
Advisors/Committee Members: Balkrishnan, Rajesh.
Subjects: Economics; Health care; Pharmaceuticals; Public health
Keywords: sickle cell disease; hydroxyurea; adherence; outcomes; costs
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15.
Cao, Xianhua.
Simultaneously targeting hypoxic cancer cells by hsp90 inhibitor and glycolysis inhibitor in pancreatic cancer therapy.
Degree: PhD, Pharmacy, 2007, Ohio State University
► Pancreatic cancer is the fourth leading cause of cancer death. Due to…
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▼ Pancreatic cancer is the fourth leading cause of cancer death. Due to the complexity of pancreatic cancer in various biochemical and genetic abnormalities especially under hypoxia, the therapeutic regimen is rather limited. Thus inhibition of heat shock protein 90 (HSP90) to simultaneously down-regulate multiple oncogenic proteins would have potential anti-pancreatic cancer effect especially under hypoxia. In addition, high glycolysis rate presents in various solid tumors due to hypoxia, which has been confirmed by positron emission tomography (PET) in human pancreatic tumor. Therefore, we hypothesize to simultaneously target the hypoxic pancreatic cancers by HSP90 inhibitor to down regulate multiple oncogenic proteins and to inhibit the energy production by glycolysis inhibitor for synergistic effect of pancreatic cancer therapy. Primary human pancreatic tumors showed constantly high expression of HSP90 and other oncogenes. The immunostaninging of tissue micro-array for 72 human pancreatic cancer patients indicated the high level of cytoplasmic staining for HSP90, p-AKT, VEGF, and HKII. HSP90 inhibitor, geldanamycin (GA), exhibited more than 10-fold stronger anti-tumor effect via induction of more client protein degradation such as HIF1á and AKT under hypoxia. Furthermore, glycolysis inhibitorsm, 3-Bromo-pyruvate (3-BrPA), showed selective inhibition of high glycolysis in pancreatic cancers under hypoxia and with the preferential inhibition of high rate of glycolysis under hypoxia, 3BrPA sensitized the anticancer effect of GA by 17 to 400-fold in pancreatic cancer cells. The synergistic anti-tumor effect of geldanamycin and 3-BrPA was confirmed in a xenograft model and RIP1-Tag2 transgenic pancreatic tumor model in vivo as measured by tumor growth, AKT degradation as the surrogate marker, and evaluated by non invasive MRI tumor imaging. Combination treatments with GA and 3BrPA showed more than 75% and 90% inhibition on the tumor growth in human pancreatinc cancer xenograft models and RIP1-Tage transgenic pancreatic tumor model, respectively. A physiological based pharmacokinetics (PBPK) and mechanism based pharmacodynamics model was further developed to characterize and evaluate the combination effect of HSP90 inhibitor and glycolysis inhibitor in pancreatic tumor models. All the in vitro and in vivo studies indicated that combination treatment with HSP90 inhibitor and glycolysis inhibitor provides a new therapeutic strategy in pancreatic tumor therapy.
Advisors/Committee Members: Sun, Duxin.
Subjects: Health Sciences, Pharmacy
Keywords: Multiple targeting; Hypoxia; HSP90 inhibitor; Glycolysis inhibitor; Combination treatment; Pancreatic cancer therapy
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16.
Carrier, Raeann Lynn.
Excitotoxicity and bioenergetics in Huntington's disease transgenic neurons.
Degree: PhD, Pharmacy, 2008, Ohio State University
► Huntington's disease (HD) is a hereditary neurodegenerative disease caused by a polyglutamine…
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▼ Huntington's disease (HD) is a hereditary neurodegenerative disease caused by a polyglutamine expansion (>39 repeats) in the huntingtin protein. HD causes loss of striatal neurons and patients develop progressive chorea, rigidity, and lack of motor coordination. We have cultured forebrain neurons from both the R6/2 transgenic mouse line (expressing an N-terminal fragment of human huntingtin with ~150 glutamines) and the YAC72 line (expressing full-length human huntingtin with 72 glutamines) to study the effect of mutant huntingtin expression on AMPA/kainate receptor-mediated neuronal signaling and cell death. Using a sensitive and selective neuronal cell death assay our lab recently developed, we found that R6/2 neurons, but not YAC72 neurons, are significantly more vulnerable to glutamate and kainate-mediated neuronal death compared to wildtype (WT) control neurons. Since calcium is a key mediator of glutamate receptor-mediated neuronal death, we measured calcium levels in response to kainate. Kainate-induced (30 second) neuronal calcium responses were significantly greater in R6/2 neurons compared to WT neurons; however, this increased sensitivity to kainate was not seen in YAC72 neurons. When we used a low-affinity fluorescent calcium indicator to monitor longer (15 minute) exposures to kainate, we revealed a subset (~20%) of neurons that exhibit very large increases in calcium. However, there were few notable differences between kainate-mediated calcium responses in HD and WT neurons under these recording conditions. Similarly, kainate-induced mitochondrial depolarization and ATP decreases were comparable in HD and WT neurons. Collectively, our results suggest that mutant huntingtin expression in young cultured neurons does not profoundly affect AMPA/kainate receptor mediated signaling. This is in contrast to the reports of robust modulation of NMDA receptor-mediated signaling and death in HD transgenic neurons. While we have focused on the short-term effect (weeks) of mutant huntingtin expression on AMPA/kainate receptor signaling, we do not know the cumulative effect of mutant huntingtin expression on both NMDA and AMPA/kainate receptor-mediated signaling over the decades of disease progression in HD patients. Whether the relatively modest potentiation of AMPA/kainate receptors that we discovered, along with previously reported effects on NMDA receptors, contribute to neuronal dysfunction in HD patients remains to be determined.
Advisors/Committee Members: Hoyt, Kari.
Subjects: Pharmacology
Keywords: excitotoxicity; calcium; huntingtin; kainate; glutamate; mitochondria
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17.
Chaves, Alysia Anne.
Mechanisms of AIDS and cocaine related cardiovascular disease.
Degree: PhD, Pharmacy, 2003, Ohio State University
► The primary focus of this thesis deals with understanding pathophysiological aspects of…
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▼ The primary focus of this thesis deals with understanding pathophysiological aspects of retrovirus (HIV/AIDS) and cocaine related cardiovascular complications. Central goals were to define important interactions between the cardiovascular and immune systems and involvement of oxidant related pathways in relevant animal models and in human tissues. Additional components of this dissertation were to define optimal conditions for cardiovascular performance assessments (contractility and electrophysiology) in mouse models and to develop novel mechanistic insights so that therapy could be further optimized. Using a relevant mouse model of retroviral pathogenesis (LPBM5, “murine AIDS” model) we observed time dependent cardiomyopathy and first-time evidence of reactive nitrogen species in cardiac tissue in this setting; we also corroborated these phenomena in a well-defined set of human tissues from HIV/AIDS autopsy cases. In subsequent investigations we found that a modest exposure of bacterial lipopolysaccharide amplified abnormalities in cardiac structure and function observed in the murine AIDS model, and that this synergistic effect was associated with increased cardiac prevalence of activated monocytes and cardiac myocyte expression of toll-like receptor 4 (TLR4, an important component of cardiac innate immunity). These observations suggest that coincident infection in humans may promote HIV-related cardiac complications. In separate studies we investigated mechanistic aspects of cocaine related cardiovascular toxicity in mice. A single dose of cocaine (30mg/kg) caused acute and protracted electrical abnormalities and protracted endothelial dysfunction in mice, analogous to clinical phenomenon observed in humans. Isolated cell experiments demonstrated that cocaine induced toxicity is related to increased cellular production of oxidants (in the absence of hypoxia). In a pilot clinical study we also investigated the effects of a standardized grape product with respect to vascular performance in normal subjects. We found that this product produced beneficial effects on endothelial function (using a noninvasive ultrasound method of evaluation) and that these were not ethanol-dependent and could protect against detrimental influences of a standard high fat meal. Collectively these studies demonstrate an important role for oxidant related and immune system mediated processes in diverse settings of cardiac and vascular dysfunction.
Advisors/Committee Members: Bauer, John Anthony.
Subjects: Health Sciences, Pharmacology
Keywords: HIV, retrovirus, LP-BM5, murine AIDS, reactive nitrogen species, cocaine, cardiovascular, endothelium, oxidants, brachial artery ultrasound, grapes
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18.
Chen, Chang-Shi.
Beyond induction of histone acetylation: the multi-facets of the antineoplastic effect of HDAC inhibitors.
Degree: PhD, Pharmacy, 2006, Ohio State University
► Histone deacetylase (HDAC) is recognized as one of the promising targets for…
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▼ Histone deacetylase (HDAC) is recognized as one of the promising targets for cancer therapy as aberrant transcriptional regulation of the epigenetic system has been linked to tumorigenesis. To date, many HDAC inhibitors have entered clinical trials in light of their high potency in inhibiting tumor cell growth without incurring significant toxicity. Although the effects of HDAC inhibitors on chromatin remodeling and transcriptional regulation are well understood, an increasing body of evidence suggests that modulation of gene expression might not be exclusively responsible for the antineoplastic effects of these agents. In the first part of this study, we demonstrate a novel histone acetylation-independent mechanism by which HDAC inhibitor induces Akt dephosphorylation in U87MG glioblastoma cells by disrupting HDAC-protein phosphatase 1 (PP1) complexes. This selective histone acetylation-independent action of HDAC inhibitors on HDAC-PP1 complexes also represents the first example of modulating specific PP1 interactions by small-molecule agents. The results of the second part of this study present the efficacy of (S)-HDAC-42, a novel HDAC inhibitor synthesized in our laboratory, in prostate cancer cells. We demonstrate that the antitumor effects of (S)-HDAC-42 are attributed to both histone acetylation-dependent and -independent mechanisms by interfering with the activation or expression status of a number of signaling targets. Together, these mechanisms provide a molecular basis to account for the efficacy of (S)-HDAC-42 in suppressing established prostate xenograft tumor growth. The third part of this study reports another transcriptional regulation-independent anticancer effect of HDAC inhibitor; the inhibition of DNA damage repair. We show that pretreatment of the Bax-deficient DU-145 cells with HDAC inhibitors increased Ku70 acetylation, thereby reducing Ku70’s DNA end-binding affinity and diminishing the cellular capability to repair DNA damage. The ability of HDAC inhibitors to modify DNA damage repair underlies the viability of their combination with DNA damaging agents as a therapeutic strategy for prostate cancer. This dissertation research characterizes two novel histone acetylation-/transcriptional regulation-independent anticancer effects of HDAC inhibitors. Moreover, we also show that these histone acetylation-dependent and -independent mechanisms underscore the pleiotropic antineoplastic effects of HDAC inhibitors at both epigenetic and cellular levels.
Advisors/Committee Members: Chen, Ching-Shih.
Subjects: Health Sciences, Pharmacy
Keywords: Histone deacetylase inhibitors; Histone acetylation-independent; transcriptional regulation-independent
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19.
Chen, Jiyun.
Discovery and Therapeutic Promise of Selective Androgen Receptor Modulators for Hormonal Male Contraception.
Degree: PhD, Pharmacy, 2005, Ohio State University
► There is an urgent need to develop new forms of contraception that…
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▼ There is an urgent need to develop new forms of contraception that men are willing to use. Currently, testosterone-based hormonal contraceptives represent the most promising approach. However, testosterone demonstrates little activity after oral administration due to rapid hepatic elimination, precluding its use in oral contraceptives for men. The long-term safety of testosterone, as it relates to psychological function, cardiovascular disease, and prostate disease, is also of concern. Non-steroidal selective androgen receptor modulators (SARMs) may provide an alternative to the use of testosterone, with the advantages of oral bioavailability, tissue selectivity, lack of influence on lipoproteins, and androgen receptor (AR) specificity. We hypothesized that SARMs would mimic the pharmacologic activity of testosterone in vivo and can safely replace testosterone as a component of hormonal male contraceptives. SARMs discovered previously demonstrated potential applications in the treatment of muscle wasting, osteoporosis, and benign prostate hyperplasia in animal models. However, low or no CNS effects were observed, which precluded their use for hormonal male contraception as a single regimen. Novel AR ligands were designed and synthesized using integrated knowledge of molecular modeling, structure-activity-relationships, and pharmacokinetics and metabolism of known SARMs. In the current studies, the abilities of these compounds to bind AR and to stimulate (agonist) or inhibit (antagonist) AR-mediated transcriptional activation (Chapter 2) were determined. Compounds with high AR binding affinity and potent stimulatory activity in transcriptional assays were further investigated in castrated rats (Chapter 3) for their pharmacologic effects. Key in vitro and in vivo structure-activity-relationships of these ligands were identified. Differences in the pharmacokinetics and metabolism between SARMs resulted in a contradiction between the in vitro and in vivo pharmacologic activity, and also provided rationale for further structural modifications (Chapter 4). Through our iterative, step-wise experimental paradigm, more potent SARMs were discovered using structural modifications of our lead compound. The effects of the potent SARMs on spermatogenesis, reproductive and peripheral organs, body composition, hormonal biomarkers, sexual behavior, and fertility were further investigated (Chapters 5 through 7). As a whole, these studies provide valuable information regarding the physiologic and pharmacokinetic factors governing the pharmacology and feasibility of SARMs for hormonal male contraception.
Advisors/Committee Members: Dalton, James T.
Keywords: testosterone; castrated; ANDROGEN; Male Rats; SARMs; C-6; C-31
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20.
Chen, Kuen-Feng.
Troglitazone: from an insulin sensitizer to a novel class of anti-cancer agent.
Degree: PhD, Pharmacy, 2005, Ohio State University
► Troglitazone (TG) hold a unique apoptosis-inducing ability, which is not found in…
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▼ Troglitazone (TG) hold a unique apoptosis-inducing ability, which is not found in other synthetic peroxisome proliferator-activated receptor gamma ligands like rosiglitazone or pioglitaozne, and we have reported that the inhibition of Bcl-2/Bcl-xL functions is a major PPAR gamma independent mechanism for apoptosis-inducing effect of troglitazone. In this study, we start from exploring an interesting drugs interaction between TG and celecoxib. Our data indicates 10 µM celecoxib can sensitize TG-induced apoptosis in PC-3 cells and HT-29 cells. This effect is not related to either cyclooxygenase-2 (Cox-2) activity of celecoxib or PPAR gamma activity of TG. In addition, TG-88, a derivative of TG with higher Bcl-2/Bcl-xL inhibitory activity also shows the same potentiation with celecoxib, suggesting the Bcl-2/Bcl-xL functions play an important role in this interaction. Our previous study identified Bcl-xL provides a survival mechanism of PC-3 cells suffered from the inhibition of PI3K/AKT signaling pathway. We hypothesize the combination of PDK1/AKT inhibition and Bcl-xL inhibition can exhibit maximal apoptosis-inducing effect in PC-3 cells. We employ OSU-03012, a PDK1/AKT inhibitor derived from celecoxib, and TG-88 to examine this premise. Our data shows OSU-03012 at 5 µM is able to potentiate 5 µM TG-88-induced apoptosis in PC-3 cells. In addition, animal studies of PC-3 xenograft model demonstrate the combination of TG-88 at 200 mg/kg/day and either OSU-03012 at 100 mg/kg/day or 200mg/kg/day can achieve maximal anti-tumor activity after 6 weeks of treatment. Furthermore, we studied another anti-cancer effect of TG, which is to sensitize the effect of TRAIL (TNF-related apoptosis inducing ligand) in cancer cells. Our data shows TG can sensitize TRAIL induced cell death in HT-29 and LNCaP cells via a PPAR gamma independent mechanism. Evidence from TG-88 and LNCaP cells with high expression of Bcl-xL indicates the inhibition of Bcl-2/Bcl-xL play a critical role in this TRAIL sensitizing effect of TG. Moreover, we sensitize HT-29 to TRAIL-induced cell death by reducing the expression of Bcl-xL in HT-29 through the supplement of small interference RNA, supporting the inhibition of Bcl-xL is able to enhance the effect of TRAIL.
Advisors/Committee Members: Chen, Ching-Shih.
Subjects: Health Sciences, Pharmacy
Keywords: Troglitazone; Bcl-2; PI3K; Akt; TRAIL; Prostate cancer
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21.
Chen, Ping.
Pharmacokinetic-Pharmacodynamic Studies Of 5-Azacytidine In Combination With Gti-2040.
Degree: PhD, Pharmacy, 2008, Ohio State University
► Leukemia is the most common blood cancer and is characterized by the…
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▼ Leukemia is the most common blood cancer and is characterized by the increased expansion of abnormal blood cells. Important insights into the pathogenesis of this disease have led to the development of a number of anti-leukemia drugs including nucleoside analogues, such as 5-azacytidine (5-AzaC), decitabine and aracytidine, and ribonucleotide reductase inhibitor such as GTI-2040. 5-Azacytidine and decitabine are hypomethylating agents that induce DNA demethylation, resulting in reactivation of hypermethylation-associated silencing of tumor suppressor genes. GTI-2040 is a 20-mer oligonucleotide inhibiting the expression of ribonucleotide reductase subunit 2 mRNA, an enzyme that has been found to be over-expressed in most cancers. Aracytidine is widely used as important cytostatic drug in the treatment for acute myelogenous leukemia. In order to support the mechanistic studies and potential combination treatment of these anti-cancer drugs, a non-radioactive, sensitive and specific LC-MS/MS method has been developed to quantify intracellular NTP and dNTP pools in cell matrices. A significant decrease in dCTP and dATP levels has been observed following GTI-2040 treatment in human leukemia MV411 cells. More importantly, GTI-2040 was found to down-regulate R2 mRNA and protein levels in a dose dependent manner. In order to evaluate the combination treatment effect of GTI-2040 and aracytidine, a sensitive HPLC method has been developed to determine the intracellular aracytidine triphosphate (Ara-CTP) level. A significant increase in intracellular Ara-CTP level has been observed after pretreatment of GTI-2040 in vitro. Further pharmacokinetics / pharmacodynamics (PK/PD) modeling and simulation of GTI-2040 and aracytidine in the cell exhibited the increase of intracellular Ara-CTP level by >2 fold. In order to characterize pharmacokinetic profile of 5-azacytidine in patients with hematologic malignancies, a simple, non-radioactive, sensitive and specific high-performance HPLC-MS/MS method has also been developed to quantify 5-AzaC in human plasma. A further transporter study revealed that the transport of 5-AzaC into cell may involve the human equilibrative nucleoside transporter 1 (hENT1). The pharmacokinetics of decitabine was well characterized by a two-compartment model. Body surface area was identified as a covariate with total systemic clearance in population pharmacokinetic studies of decitabine in leukemia patients. These results provide valuable insights in clinical development of GTI-2040, 5-AzaC, aracytidine and decitabine as a single agent or in combination with other drugs.
Advisors/Committee Members: Chan, Kenneth.
Subjects: Biomedical research; Chemistry; Oncology; Pharmaceuticals; Pharmacology
Keywords: pharmacokinetic pharmacodynamic GTI-2040 5-azacytidine HPLC-MS/MS HPLC-UV Ara-CTP decitabine
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22.
Chiu, Shihjiuan.
Receptor-mediated DNA-based therapeutics delivery.
Degree: PhD, Pharmacy, 2005, Ohio State University
► The objective of this dissertation was to develop and evaluate receptor-mediated non-viral…
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▼ The objective of this dissertation was to develop and evaluate receptor-mediated non-viral delivery systems for DNA-based therapeutics. Novel strategies might prove critical for the in-vivo performance of receptor-targeted vectors. Continued efforts in optimization of receptor-mediated delivery systems may lead to the development of tumor-specific vehicles for DNA-based therapeutics delivery and promote the advancement of clinical translation of cancer gene therapy. In Chapter 2, a non-viral, PEI-based, HER2-targeted gene transfer vector was developed. The anti-HER2 antibody (Herceptin®) was conjugated to PEI and polyplexes were shown to selectively deliver plasmids to HER2-overexpressing cells with high resistance to serum. Herceptin/PEI polyplexes exhibited promising HER2-receptor-specific gene transfer properties. In Chapter 3, an ethanol dilution method for the preparation of ODN was developed. This method provides a suitable platform to prepare receptor-targeted-ODN-containing liposomes. The small size, low toxicity, and, more importantly, high encapsulation efficiency of ODNs at optimized conditions are important characteristics for the development of DNA-based therapeutics delivery systems. In the next two chapters, similar method was applied to other systems including ODNs and siRNAs with high molecular weight target-ligands. The aim of Chapter 4 was to develop a targeted ODN(G3139)-containing liposome formulation that can efficiently and specifically delivery ODNs to leukemias. Transferrin receptors were overexpressed in many tumor and leukemia cells. A Tf-targeted liposomal formulation of antisense G3139 was evaluated in K562 leukemia cells, which exhibited excellent characteristics in terms of particle size, loading efficiency, colloidal stability, and vehicle toxicity. Furthermore, this formulation was very efficient in antisense delivery, showing excellent bcl2 down-regulation efficiency and TfR specificity. In Chapter 5, similar strategy was applied to siRNA delivery. Desferrioxamine(DFO) was used to up-regulate TfR in K562 cells. The data demonstrated that DFO pretreatment increased the uptake of TfR-targeted siRNA in K562 cells and exhibited higher luciferase downregulation effect. Tf-targeted siRNA formulation with DFO pretreatment was a highly efficient delivery vehicle for siRNA for leukemias that express TfR. This formulation provides the prospect of more selective targeting effect in association with increased intracellular concentrations in target cells. More future studies such as optimization and in-vivo studies are needed for this formulation to work clinically.
Advisors/Committee Members: Lee, Robert J.
Subjects: Health Sciences, Pharmacy
Keywords: Gene delivery, antisense delivery, Her2, Herceptin, Folate, Transferrin, targeted delivery
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23.
Chuang, Hsiao-Ching.
Mechanistic Validation of Potential Anti-Breast Cancer Therapeutics.
Degree: PhD, Pharmacy, 2012, Ohio State University
► Breast caner is a heterogeneous disease and this makes breast cancer a…
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▼ Breast caner is a heterogeneous disease and this makes breast cancer a difficult disease – different patients need different therapies. According to the histopathological classification, breast cancer could be divided into three distinct subtypes: ER-, PR-positive; HER2-positive; and those tumors without ER, PR or HER2 expression (triple negative breast cancers, TNBCs). The ER-, PR-positive patients could be treated with anti-estrogen therapy, including tamoxifen and aromatase inhibitors. The gold standard treatment for HER2-positive patients is trastuzumab. These therapies all show favorable effects. TNBC is totally different from previous two types: having unique gene profiling, aggressive behavior and poor prognosis. Unfortunately, the only available therapeutic option for TNBC, until recently, was chemotherapy. Further studies for developing the treatment of TNBCs are essential and urgent. In the first part of this dissertation work, α-tocopheryl succinate was chosen as a leading compound to develop potent antiadhesion agents. Adhesion is an essential step for tumor metastasis; therefore, agents with the ability to block adhesion may be able to suppress tumor metastasis of breast cancer patients. Our structural optimization led to compound 5 which exhibited an-order-of-magnitude higher potency than α-tocopheryl succinate in blocking the adhesion of 4T1 metastatic breast cancer cells to extracellular matrix proteins. Evidence indicates that the ability of compound 5 to block cell adhesion and migration was attributable to its effect on disrupting focal adhesion and actin cytoskeletal integrity by facilitating the degradation of focal adhesion kinase. Interactions between tumor cells and the ECM in the tumor microenvironment have been increasingly recognized as critical modulators of the metastatic potential of tumor cells. Consequently, the ability of compound 5 to block such interactions provides a unique pharmacological tool to shed light onto mechanisms that govern cell adhesion and tumor metastasis. In the second part of this dissertation work, we focused on the mechanistic validation of different poly (ADP-ribose) polymerase (PARP) inhibitors. Recent results of a randomized phase II clinical trial showed that BSI-201 when added to platinum-containing combination chemotherapy statistically significantly improved the outcome of metastatic TNBC patients relative to chemotherapy alone. Although PARP inhibitors may represent the first “targeted treatment” for TNBC, the mechanism(s) by which the different PARP inhibitors cause cell death remains unknown. In this study, we investigated the cellular mechanism of four PARP inhibitors in three different TNBC cell lines. Our examination of the antitumor activities of four clinically relevant PARP inhibitors in TNBC cells indicates the involvement of different mechanisms of action beyond PARP inhibition among these agents. The studies presented here provide two novel findings: identification of a novel compound with potent antiadhesion activity and using in vitro model to identify the mechanisms of action beyond PARP inhibitors. This provides the rationale for how to use these individual PARP inhibitors in clinical.
Advisors/Committee Members: Chen, Ching-Shih.
Subjects: Biomedical Research; Pharmacy Sciences
Keywords: α-tocopheryl succinate; anti-adhesion; triple-negative breast cancer; PARP inhibitor
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24.
Clark, Kelli J.
Temperature and species comparisons of Benzocaine pharmacokinetics, metabolism and physiologically based pharmacokinetic model within Channel Catfish, Ictalurus Punctatus, and Yellow Perch, Perca Flavescens.
Degree: PhD, Pharmacy, 1999, Ohio State University
► Benzocaine, a local anesthetic for mammals, has potential for use as a…
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▼ Benzocaine, a local anesthetic for mammals, has potential for use as a general anesthetic in finfish. Its pharmacokinetics, metabolism, and residue profiles were characterized to support its approval in fish. To compare interspecies and temperature differences of these parameters channel catfish were studied at 16, 21, and 26°C and yellow perch at 16°C. The feasibility of "crop grouping" was investigated with a physiologically based pharmacokinetic (PBPK) model as a means to reduce the amount of testing required for aquaculture drug registration.Plasma concentration-time profiles and residue depletion profiles of benzocaine in fish tissues and fluids were characterized after fish were administered an intraarterial constant-rate infusion of 60.5 μmol/kg benzocaine for 30 minutes. The tissue partition coefficients for benzocaine and its main metabolites were determined by fish exposed to 18.4 μmol/L benzocaine bath for 24 hours. Benzocaine, acetylbenzocaine, p-aminobenzoic acid, and acetyl-p-aminobenzoic acid concentrations were determined by reverse isotope dilution using HPLC and LS counting. The PBPK model was comprised of seven tissue groups connected by a parallel circulatory system, in which elimination was by liver and trunk kidney metabolism, and branchial excretion.Benzocaine disappearance from plasma conformed to a two-compartment model. Comparison between benzocaine metabolic clearances and total body clearances implied that blood flow across the gills, not metabolism, was its primary route of elimination. By 48 hours, less than 2.1% of the dose remained in the fish, of which a small percentage was in the white muscle (edible tissue). The benzocaine blood-to-water concentration ratio was 2.17-2.80 for catfish and 5.47 for perch. The magnitude of the tissue partition coefficients suggested that tissues would not retain benzocaine if elimination were perfusion rate limited. Benzocaine was 63-76% nonsaturable bound to plasma proteins. In fact the combined low affinity, high capacity and high affinity, low capacity plasma protein binding accounted for the rapid initial elimination of benzocaine followed by a longer terminal elimination. The excellent correspondence between experimental and simulated data suggested that the PBPK model was representative of the "true" physiology of fish with regard to benzocaine exposure.
Advisors/Committee Members: Hayton, William L.
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25.
Coss, Christopher C.
Selective Androgen Receptor Modulator (SARM) Action: Androgen Therapy Revisited.
Degree: PhD, Pharmacy, 2008, Ohio State University
► Despite continuing advances in the clinical development of selective androgen receptor modulators…
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▼ Despite continuing advances in the clinical development of selective androgen receptor modulators (SARMs) for male hypogonadism, osteoporosis, muscle wasting and myriad diseases of the prostate, mechanism remains controversial. To date, mechanistic work in the selective hormone receptor modulator (SRM) field has been dominated by selective estrogen receptor modulators (SERMs) where a full understanding of SERM action contributed to the development of second generation molecules with better selectivity and reduced side effects. It follows that a better understanding of SARM action could lead to improvements in rationale SARM design and even molecules tailor made for specific patient populations or disease states. The studies described herein were carried out to shed light on the molecular mechanism of aryl propionamide SARM action resulting in full efficacy in anabolic tissues (muscle and bone), while sparing androgenic tissues (prostate and skin). To this end genome wide androgen receptor (AR) promoter binding and transcriptional profiling in LNCaP prostate cancer cells was performed. In these experiments, the primary prostatic androgen 5α-dihydrostestosterone (DHT) was compared to aryl propionamide SARMs, revealing largely overlapping but distinct modes of action. These works support the existence of qualitative differences, not solely due to potency, underlying SARM mechanism. A renewed therapeutic interest in androgens has created an opportunity to re-evaluate side effects that have prevented wide scale androgen therapy. Seemingly pro-athrogenic lipid profiles result from androgen treatment though links to cardiovascular disease are largely observational and conflicting. Also studies showing androgens to be hepatotoxic are confounded by existing disease states and a heavy focus on anabolic steroid abusers. Nevertheless, the dogma surrounding dangers of androgen administration contribute to clinicians’ apprehensions in using anabolic agents to treat a cadre of human ailments. The studies described herein characterize these effects for aryl propionamide SARMs arguing that elevations of serum ALT, thought to reflect liver toxicity, are actually the result of androgen mediated gene expression. Reductions in serum HDL-C were found to be tightly linked with anabolic efficacy in short term studies, but flexibility in the aryl propionamide pharmacophore coupled with high amenability to varied formulations offer hope toward future SARM therapies.
Advisors/Committee Members: Dalton, James.
Subjects: Pharmacology
Keywords: SARM; androgen; HDL-C; LNCaP; androgen pharmacology; prostate cancer; cholesterol; selective androgen receptor modulator
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26.
Cox, James Eric.
Characterization of NonR, an esterase that confers nonactin resistance.
Degree: PhD, Pharmacy, 2004, Ohio State University
► Nonactin is the parent compound of the macrotetrolide class of antibiotics, atypical…
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▼ Nonactin is the parent compound of the macrotetrolide class of antibiotics, atypical cyclic polyethers, consisting of both enantiomers linked via four ester linkages in a (+)(-)(+)(-) manner. The higher macrotetrolide homologs of nonactin are made up of successive substitutions of nonactic acid with homononactate or bishomononactate. The macrotetrolides act as ionophores, forming complexes with both monovalent and divalent ions. Organisms that produce antibiotics as a defense mechanism need to protect themselves from their own biosynthesis products. Self-protection is achieved using many methods such as modification of the antibiotic itself, modification of the cellular target, removal of the produced antibiotic to specific binding proteins, or changes in the cell wall. Many species employ several of these methods simultaneously, incorporating antibiotic modification steps into the biosynthesis pathway and using the other methods to offer layers of resistance. A genetic resistance element conferred tetranactin resistance to a macrotetrolide sensitive host. The genetic element was cloned from the producer, Streptomyces griseus subsp. griseus. By sequence analysis the protein product, NonR appeared to be an esterase. This work describes the subcloning of the gene nonR, its expression in a heterlogous host, and examination of the activity of the expressed protein. Expression and purification of the protein NonR, was accomplished using an affinity tag; NonR proved to be labile, losing activity throughout the purification process. NonR hydrolyzes the the ester bonds of nonactin stereoseletively, cleaving between the acid of the (-)-nonactate and the alcohol of the (+)-nonactate. The order of hydrolysis is first the closed chain parent, nonactin, is cleaved to an open chain tetramer, followed by cleavage of the tetramer to two dimer species. Under conditions of high protein concentration, NonR will hydrolyze the dimer species to the monomer, nonactic acid. This hydrolysis causes nonactin to lose its biological activity. To meet our synthesis need we set out to increase the yields of nonactin that is produced by fermentation. By a mix of strain selection, recipe and process improvement, nonactin production was improved from 0.1 g/L in stirred tank reactors to 4 g/L.
Advisors/Committee Members: Brueggemeier, Robert W.
Subjects: Chemistry, Biochemistry
Keywords: NonR; esterase; self-resistance; NonD; NonL; protein expression; stereoselectivity; nonactin
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27.
Cui, Yong.
Enhanced Release of Lidocaine From Supersaturated Solutions of Lidocaine In A Pressure Sensitive Adhesive.
Degree: PhD, Pharmacy, 2003, Ohio State University
► Transdermal systems consisting of a pressure sensitive adhesive (PSA) supersaturated with drug…
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▼ Transdermal systems consisting of a pressure sensitive adhesive (PSA) supersaturated with drug were studied with the objective of enhancing drug release. Lidocaine (LC) and Duro-Tak®87-2287 (PSA) were the model components. In vitro release of LC through a composite membrane consisting of multiple layers of cellulose membrane and a silicone membrane was significantly higher from supersaturated LC/PSA systems compared to systems in which drug had crystallized. Drug loading was an important factor influencing the release of LC from the systems. Hydration of the LC/PSA systems may reduce drug release by promoting crystallization of the supersaturated systems. The physical stability of the systems was evaluated kinetically and thermodynamically using thermal analysis and then applying theories of nucleation, e.g., the Fisher-Turnbull equation; and phase transformation, e.g., the Avrami equation. It was found that nucleation rather than the crystal growth process governed crystallization of LC from the supersaturated systems. Nucleation is a diffusion-controlled process, which is dependent on the viscoelastic properties of the PSA medium. Crystallization of LC in the PSA systems had a two-phase temperature dependence with the values of kinetic parameters, such as the Avrami exponent and the Avrami constant, remaining constant over a low temperature range. Over a higher temperature range, however, the crystallization behavior of LC cannot be explained by the conventional Avrami theory, and it was found that a time dependent nucleation rate may account for this behavior. The physical chemical properties of LC/PSA systems were characterized using thermal analysis and FT-IR. The thermodynamic state of the supersaturated systems was evaluated from the composition dependence of the glass transition temperatures, and the LC/PSA interactions were characterized by FT-IR. An intermediate interaction between LC and the PSA was found, resulting in a conformation entropy relaxation of the polymer systems. LC is actively involved in the relaxation of the PSA throughout the composition range. This may contribute to the physical stability of the supersaturated LC/DT2287 systems by reducing the amount of free LC in the systems.
Advisors/Committee Members: Frank, Sylvan G.
Keywords: Transdermal drug delivery, Supersaturation, Pressure sensitive adhesive, Lidocaine, Crystallization kinetics, Physicalchemical characterization
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28.
Dai, Guowei.
Pharmacokinetics,pharmacodynamics and metabolism of BCL-2 antisense phosphorothioate oligonucleotide G3139 (Genasense).
Degree: PhD, Pharmacy, 2005, Ohio State University
► Overexpression of the anti-apoptotic protein Bcl-2 has been found in about half…
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▼ Overexpression of the anti-apoptotic protein Bcl-2 has been found in about half of human cancers. G3139 is an 18-mer phosphorothioate antisense oligonucleotide designed to bind to the first six codons of the open reading frame of the human Bcl-2 mRNA. In this project, the preclinical and clinical pharmacokinetics, pharmacodynamics and metabolism of this novel therapeutics were investigated. A novel, ultrasensitive, nonradioactive hybridization ELISA method has been developed and validated for quantification of G3139. Plasma pharmacokinetics of G3139 in acute myeloid leukemia (AML) patients was characterized and found to fit a two-compartment open infusion model. There was no major pharmacokinetic interaction between G3139 and concomitant chemotherapeutic agents. Robust intracellular concentrations of G3139 in bone marrow (BM) and peripheral blood mononuclear cells obtained from treated AML patients were achieved and a correlation between the Bcl-2 mRNA/protein down-regulation and disease response was found. A higher median intracellular concentration of G3139 was detected in the complete responders as compared with non-responders. Cellular uptake and distribution of G3139 was studied in K562 cells. When exposed to free G3139, only low intracellular concentrations of G3139 were found in the cells with no significant suppression of Bcl-2 mRNA. In contrast, a 10 to 25-fold increase of the intracellular G3139 was observed when G3139 was delivered with cationic lipids. Dose-response curve shows that G3139 concentration that produces 50% down-regulation was 0.29 ìM. Two in vitro PK/PD models were developed for AML cells NB4, which describe the relationship between drug exposure and target down-regulation reasonably well. A novel ESI LC/MS/MS method has been developed. Using this method, several chain-shortened G3139 metabolites were identified in mice, rats and humans, implicating the involvement of 3’-exonuclease in G3139 metabolism. In the mouse, tissue distribution is extensive and the highest concentrations were found in kidneys, liver, spleen and BM. Metabolite kinetics were modeled and they appear to follow formation-limited kinetics. The results from these studies have provided a better characterization and understanding of disposition and pharmacological roles of G3139 and other antisense therapeutics.
Advisors/Committee Members: Chan, Kenneth K.
Subjects: Health Sciences, Pharmacy
Keywords: Bcl-2 antisense; G3139; Pharmacokinetics; Pharmacodynamics; Metabolism; Acute Myeloid Leukemia; Tandem mass spectrometry; ELISA
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29.
Davis-Ajami, Mary Lynn.
The association between joblessness and adult working age diabetic oral antidiabetic medication adherence and health services utilization.
Degree: PhD, Pharmacy, 2010, Ohio State University
► Background: Diabetes (DM), a costly, increasingly prevalent chronic disease represents one of…
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▼ Background: Diabetes (DM), a costly, increasingly prevalent chronic disease represents one of the leading causes of death and disability in the US. Declining macroeconomic conditions, unemployment, or work force non-participation may affect relationships between cost constraints, medication use, and health services utilization. Few studies assess associations between being without work and medication adherence or health services utilization for diabetics residing in the US. The objective of this preliminary, investigational research was to assess associations between joblessness and US adult working age diabetic oral anti-diabetic (OAD) medication adherence and health services utilization after controlling for demographic characteristics and clinical factors. Methods: A population based retrospective longitudinal fixed effects panel design using pooled MEPS data for the years 2001-2007 were used to estimate associations between joblessness and OAD medication adherence, as well as health services utilization. Adherence was measured using the proportion of days covered (PDC). Individuals with PDC > = 0.80 were classified as adherent. Utilization outcomes assessed associations between joblessness and the likelihood and number of all cause, DM disease specific and diabetic complication related emergency department, in-patient hospitalization, out-patient, and office based visits. Individuals age 24-59 with an ICD-9-CM code for DM, were included in the study. Pregnancy, seasonal job status, and individuals prescribed long term insulin were excluded from the study. Covariates included age, family size, gender, educational attainment, ethnicity, race, marital status, household income as a fraction of the poverty line, employment status, insurance status and geographical region, metropolitan statistical area, the Enhanced Charlson Co-morbidity Index, body mass index, and smoking status. DM related complications were classified as eye, neurological, renal, macrovascular and microvascular. Descriptive statistics and multivariate regression analysis that accounted for the MEPS complex survey design were used to assess the study’s main objectives. Results: 2,678 individuals (mean age 48.7, mean BMI 31.5, 51% female, 15% Hispanic, 19% Black, 10% uninsured with 50% of the uninsured employed, 34% poor, near poor, or low income, 42% jobless with 30% of the jobless without work for all 5 interview rounds) met inclusion criteria with a weighted stratified sample projected population estimation of 20,656,899. Reasons cited for no job were: 72% waiting to start a new job, 19% unable to work due to illness or disability, 3% taking care of home or family, 3% retired. An estimated 55% were non-adherent. Medication adherence showed statistically significant associations between joblessness and lower PDC and an increased likelihood of being non-adherent. Utilization showed statistically significant associations between joblessness and increased likelihood of all cause ED, hospitalization, and outpatient utilization and increased number of ED, outpatient and office-based utilization, as well as increased likelihood and number of EDC-9-CM DM coded office based visits. Collaterally, those of Hispanic origin were identified as a particularly vulnerable group. Conclusion: The results suggest suboptimal OAD medication adherence with joblessness significantly decreasing the likelihood of being adherent. Significant differences were found between jobless and employed person’s likelihood and number of all-cause and DM disease specific ED, hospital, out-patient and office-based utilization. These findings merit further investigation.
Advisors/Committee Members: Nahata, Milap.
Subjects: Health care; Pharmaceuticals
Keywords: diabetes; diabetic; type II diabetes; medication adherence; oral antidiabetic medication; health care utilization; health services utilization; unemployment; jobless; joblessness; employed
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30.
Delfin, Dawn Athelsia.
A novel and potent antileishmanial agent: in silico discovery, biological evaluation and analysis of its structure-activity relationships.
Degree: PhD, Pharmacy, 2007, Ohio State University
► Leishmaniasis is a parasite disease which currently afflicts 12 million people worldwide…
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▼ Leishmaniasis is a parasite disease which currently afflicts 12 million people worldwide with two million new cases annually. Without treatment, visceral leishmaniasis is 100% fatal while other forms can be severely disfiguring and debilitating. Novel therapies are urgently needed; current treatments possess many negative attributes such as toxicity and loss of effectiveness due to resistance. Previous research demonstrated promising antileishmanial activity of several dinitroaniline sulfonamides. A QSAR evaluation of these compounds was performed using Catalyst software, generating a three-dimensional pharmacophore, and highlighting the specific functionalities of the compounds that confer antileishmanial activity. This pharmacophore was used to search the Maybridge database. Nineteen hits were tested for antileishmanial activity. Two compounds were highly active while another five compounds were moderately active (IC50 = 21-39 µM). The most potent compound, BTB06237 was also able to reduce parasite burdens in L. mexicana-infected J774 macrophages. TEM and fluorescence microscopy have shown that the single parasite mitochondrion becomes dilated and fragments into intensely staining, disjoined spheres following incubation with BTB06237. It appeared to cause mitochondrial membrane potential disruption, in parallel to that observed in parasites treated with the uncoupler FCCP. These data imply that BTB06237 disrupts mitochondrial structure and function. The presence of nitro groups on BTB06237 indicates that BTB06237 may increase the level of reactive oxygen species (ROS) in the parasites through redox cycling. Indeed, assays on treated parasites showed increased levels of ROS. Additionally, a structure-activity relationship study was performed by synthesizing and evaluating the antileishmanial activity of 16 total analogs. Regarding the phenylsulfanyl ring, antileishmanial potency was preserved regardless of the substituents, but loss of aromaticity lead to loss of activity. The dinitrobenzyl ring, on the other hand, was less flexible, requiring two nitro groups and an additional electron-withdrawing group for activity against the parasites. Altogether, these results indicate that BTB06237 is an intriguing lead compound against Leishmania that likely participates in redox cycling. The redox cycling then induces ROS inside the parasites, interfering with mitochondrial function, and ultimately killing the parasites. This work also demonstrates the utility of in silico methods for identifying lead compounds against Leishmania parasites.
Advisors/Committee Members: Werbovetz, Karl A.
Keywords: Leishmania; parasitology; drug discovery; QSAR; pharmacophore; database screening; mitochondria; structure-activity relationships
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