▼ Ambroxol is an active metabolite of bromexine that has been proven to possess a great bronchosecretolytic effect and has been used to treat infants from 0 to 6 month and children till over 12 years of age, as well as adults. My thesis research was aimed to detect potential adverse effects of ambroxol on development using zebrafish embryos/larvae as a model and to investigate the possible involvement of the zebrafish cytosolic sulfotransferases (SULTs) in the protection against the possible adverse effects. Developing eggs at 24 hpf, 48 hpf, and 72 hpf were exposed to different concentrations (1mM, 0.5 mM, 0.25 mM, 0.125 mM, and 0.05 mM) of ambroxol in triplicate and observations were made daily for eleven consecutive days. Ambroxol induced cardiac edema and bradycardia at different stages of development in a dose-dependent manner. Enzymatic assay of purified zebrafish SULTs showed significant sulfation of ambroxol by SULT2 ST1 and SULT3 ST1, 2, 3, 4, and 5. How these SULTs may be involved in protection against the adverse effects of ambroxol remains to be clarified. Advisors/Committee Members: Liu, Ming-Cheh.

▼ Hypoxia within a solid tumor is known to cause resistance to radiation therapy. It is the biggest problem that cancer patients face during radiation treatment. In this study, a potential hypoxic cell sensitizer, AB2, was synthesized and then investigated for its ability to sensitize hypoxic cells to radiotherapy. The study began with the chemical synthesis of AB2 in a three step process. The structure of AB2 contains a 2-nitroimidazole and an aza-anthracenedione which are both important to the predicted activity of AB2. Once the synthesis of AB2 was complete the biological characterization of the compound was studied. These experiments began by demonstrating that anoxia in 8226 multiple Myeloma cells caused resistance to radiotherapy. Once resistance was demonstrated the effects of AB2 were tested. AB2 was administered to both anoxic and oxic 8226 multiple Myeloma cells and the cells were exposed to radiation. AB2 caused an increase in the cell death in anoxic cells as well as oxic cells that were irradiated. However the cell death in anoxic cells was higher than in oxic cells. Cell death also increased in anoxic and oxic cells that were not irradiated and were simply administered a dose of AB2. A dose response experiment showed that as the dose of AB2 increased the amount of cell death also increased. All of the data gathered from this study suggests that AB2 is a potential drug for cancer therapy. AB2 appears to have selectivity to anoxic cancer cells and improves the cell death from radiation exposure. Further research is necessary to in order to gain a better understanding of the biological characteristics of AB2. More in vitro and in vivo studies should be done to examine the toxicity of the compound and find the most effective dose. The use of a radiosensitizer, such as AB2, in combination with radiotherapy in cancer patients could eliminate the resistance that hypoxia causes to radiotherapy. The data from this study shows that AB2 is a promising compound for improving cancer therapy. Advisors/Committee Members: Hacker, Miles.

▼ This study examines the clearance of five therapeutic drugs, carbamazepine, phenytoin, procainamide, quinidine, and theophylline, in an in vitro hepatocyte suspension. Parent drug concentration was measured via fluorescence polarization immunoassay or high performance liquid chromatography as a function of time. Parent drug disappearance data were used to calculate linear one-hour disappearance (parent drug activity) and intrinsic in vitro clearance rates. The in vitro clearance value was scaled to a prediction of human in vivo hepatic clearance using the well-stirred model. No correlation between parent drug activity or predicted in vivo hepatic clearance and reported donor characterization was observed. Observed intrinsic in vitro clearance rates were unsuccessful at accurately predicting in vivo hepatic clearance. Therefore, these results are inconclusive regarding the potential use of cryopreserved hepatocytes for the preclinical estimation of human in vivo hepatic clearance. Advisors/Committee Members: Byers, James P.

▼ Breast cancer is the second most frequently diagnosed cancer and it ranks second among cancer deaths in women. The anthracycline antibiotic doxorubicin, more commonly known as Adriamycin, is a drug widely used in breast cancer chemotherapy. The mechanism of action of this particular drug is still somewhat unclear, although it is thought to interrupt the progression of a known DNA unwinding enzyme, Topoisomerase II. Another drug used in breast cancer is the anthracenedione, Mitoxantrone. This drug is used in the treatment of metastatic breast cancer. Mitoxantrone is also a Topoisomerase II inhibitor. In some cases, patients become resistant to chemotherapies or have malignancies that recur. These recurrences are sometimes due to cells that are resistant to the current chemotherapeutic tactic being applied. These cells that resistant express P-glycoprotein. P-glycoprotein is an ATP-dependent efflux pump that has evolved to remove harmful substances from cells. In the case of chemotherapy failure, it is a good chance that patients exhibit an overproduction of P-glycoprotein in their tumor cells. This leads to a population of cells that has the unique ability to rid itself of drug and express multi-drug resistance.Although these chemotherapeutic agents are effective anticancer drugs their efficacy is limited by drug-induced cardiotoxicity and therapy must be stopped once a patient has received a cumulative dose of 550mg/m2. Researchers have sought other equally effective Topoisomerase II inhibitors that lack the cardiotoxicity. The development of 9-aza-anthrapyrazoles has led to drugs that are not only active against breast cancer, but are non-cardiotoxic. Furthermore, an interesting observation has been made in which compounds containing two terminal tertiary amine side chains, as seen in the compounds BBR3378 and BBR3409, are active in PGP expressing MCF-7 cells. The purpose of this thesis is to determine the potency of these novel cancer drugs and also to determine intracellular drug distribution in cells. The two colorimetric assays that were used during this project were the MTT cell proliferation assay and a trypan blue exclusion assay. Advisors/Committee Members: Hacker, Miles P.

▼ Background: Diabetes patients are usually at increased risk of developing cardiovascular diseases (CVDs). The treatment with statins is known to reduce cardiovascular risk in the secondary prevention of CVDs. Several observational studies have shown that the patients on statin therapy have low adherence. Low adherence is an important issue which has serious health implications like increased morbidity and mortality. Objectives: The main objectives of this study were to determine the adherence with statins among the University of Toledo (UT) employees and their dependents with diabetes and to study the effects of independent variables [age, co-payment, gender, location (main vs. health science campus), and adherence with the diabetes medications] on adherence with statins. Methods: This study was a retrospective, longitudinal observational study. UT employees and their dependents pharmacy claims data was used for the study. Adherence with statins was determined in 180 day and one year observation periods for those patients who filled prescriptions for statins in addition to prescriptions for oral hypoglycemic drugs (OHDs) during the study period. Medication possession ratio (MPR) for statins was calculated and used as the dependent variable (MPR < 80% - non-adherent, MPR >= 80% - adherent). Descriptive statistics were used to describe the study population. Logistic regression was used to study the effects of independent variables on adherence with statins. Results: One hundred and ninety-three patients were included in the 180 day analysis, while 150 patients were included in the one year analysis. The mean adherence with statins was 0.80 and 0.78 over the 180 day and one year observation periods, respectively. About 64% of patients were adherent to statin medications with MPR ≥ 80% during the 180 day observation period. This adherence rate decreased to 60% of patients at the end of one year. In the regression model, adherence with diabetes medications was significantly positively related with adherence with statin medications. Conclusion: Adherence with statins was found to be suboptimal among the study population. This presents an increased risk of developing cardiovascular complications among this population, which can lead to increases in the healthcare costs for the university. The university should further investigate the reasons for non-adherence in this population and interventions should be designed to improve adherence. Improved adherence can help in reducing overall healthcare cost for this self-insured organization. Advisors/Committee Members: Holiday-Goodman, Monica.

▼ Introduction - Entrepreneurship is the ability of an individual to start one’s own business, undertaking all the risks related to that business. Many business schools have entrepreneurship courses which encourage students to consider this career option. Today, along with organizational careers, entrepreneurship is also considered as a viable choice by many business students. Objective - To examine the factors that determine the intent and attitudes of pharmacy students towards ownership of a pharmacy using the Theory of Planned Behavior. Methods - Students in year five of a six year degree program of the colleges of pharmacy of the University of Findlay (UF) and the University of Toledo (UT) were asked to fill out a survey in class. The course professors distributed the surveys and collected them immediately after the surveys were completed. No interaction took place between the researcher and the students. Results - Confirmatory factor analysis was done to get an overall score of 0.7 and above to get a reliable questionnaire. Linear regression (LR) results showed that subjective norms (p>.000) and attitude (p>.000) had a significant relationship with intent at both universities. Only at the University of Findlay was a significant relationship found between perceived behavioral control and intent (p=.006). ANOVA and t-test results demonstrated that the question “Did any of your courses have an entrepreneurship component in it” significantly influenced intent at both the universities. Age and income did not significantly influence intent at either university. Gender and participation in an entrepreneurship course significantly influenced intent only for the University of Toledo students. Conclusion – Intent was found to have a significant relationship with attitude and subjective norms at both the universities. Adding courses to the pharmacy curricula might encourage students pursue ownership in the future. Advisors/Committee Members: Holiday-Goodman, Monica.

▼ It has been recently documented that subchronic exposure of rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)causes oxidative damage in various brain regions. In this study, we have investigated the effects of TCDD on the levels of biogenic amines in the rat brain after subchronic exposure. The rats were exposed to TCDD for 13 weeks at 2 different concentrations (22 and 46 ng/kg/day). At the end of the exposure period the animals were euthanized and brain tissue samples were collected from 4 different brain regions: Hippocampus (H), Cerebral Cortex (Cc), Midbrain (MB), and Cerebellum (C). These samples were kept at -80°C. These tissue samples were analyzd for different biogenic amines including NE, DA, DOPAC, 5-HIAA, 5-HT and HVA using a high performance liquid chromatography system with an electrochemical detector. The results show significant increases in DA, DOPAC and HVA in the hippocampus and cerebral cortex but not in the midbrain or the cerebellum in response to the 22 and 46 ng/kg/day doses. However, NE was significantly increased in the hippocampus and cerebral cortex in rats treated with 46 ng/kg/day, it was also increased in the midbrain and cerebellum at both the 22 and 46 ng/kg/day doses. These results are important since many of the TCDD-induced neurotoxic effects in humans are associated with functions of the brain regions found to be affected in this study. Advisors/Committee Members: Byers, James P.

▼ Diabetes is a leading cause of morbidity and mortality in the United States. The American Diabetes Association has put forth guidelines to screen and prevent the progression of diabetes. However, lack of access to adequate health care can hinder treatment options for individuals diagnosed with diabetes. A number of organizations help uninsured individuals by providing access to health care. Toledo Lucas County CareNet has provided healthcare access to uninsured residents since 2003. The presented study focused on evaluating outcomes related specifically to CareNet members diagnosed with diabetes. The objectives of this study were to determine the percentage of patients with Type 2 diabetes that reached ADA recommended guidelines in A1c, blood pressure (Systolic and Diastolic) values, and lipid levels (HDL and LDL), and to determine the factors related to goal attainment. The factors studied were age, gender, race/ethnicity, height, weight, tobacco use, and pharmacotherapy. The study design was a retrospective chart review. Patient charts of Toledo Lucas County CareNet clients were reviewed. Data were collected from three major health systems in Toledo, Ohio, where CareNet members receive medical services. The results showed 179 patients met the inclusion criteria out of 712 charts reviewed from the three respective health centers. Goal attainment was observed in all clinical markers. About 62% of CareNet members in the study met goal in A1c, 60% of members met goal in systolic blood pressure, and 75% met goal in diastolic blood pressure. In regard to HDL, 40% of men met goal compared to 77% of women. Over 51% of members met goal in LDL value. T-test results for changes in A1c were significant for participants greater than 40 years of age compared to those less than 40 years of age. Similarly, ANOVA results showed significant results for changes in A1c in African Americans compared to other races. The regression analysis model explained about 21% of variance, and age was estimated to be the strongest predictor for A1c improvement. The findings for regression analysis were statistically significant at p=0.036. The overall model for diastolic blood pressure was R=0.281, p=0.013, which means that about 28% of variance was explained by the model. Gender and age were estimated to be significant predictors for diastolic blood pressure improvement. Males showed lower improvement in diastolic blood pressure compared to females. Results obtained in this study were consistent with the previous literature. In conclusion, the ADA guidelines for goal attainment for A1c, blood pressure values and lipid levels were met by the majority of CareNet patients with diabetes. Advisors/Committee Members: Holiday-Goodman, Monica.

▼ The purpose of this study was to examine the nature of the solid-state interaction between ibuprofen and nicotinamide and determine the solubility enhancement achieved by using nicotinamide as a hydrotropic agent and develop a suitable efficacious formulation. Ibuprofen-nicotinamide binary mixtures were prepared by solvent evaporation method. DSC studies suggested complex formation between ibuprofen and nicotinamide with 1:1 stoichiometry in solid state. UV-Visible spectroscopy suggested that the interaction was weak. Disappearance of the broad hydrogen bonding peak in the FTIR spectrum for the complex predicted greater solubility for the complex. Proton NMR studies ruled out the possibility of any chemical interaction between the two compounds. PXRD and microscopic studies showed that the crystallinity of the complex was remarkably reduced. All the studies predicted greater solubility for ibuprofen in complexed form. The HPLC studies showed that solubility was enhanced 62 times in the suspension when the concentration of nicotinamide was 13.3 mg/mL. Advisors/Committee Members: Alexander, Kenneth S.

▼ Medical expenditures can be controlled by improving patient adherence to medications. Various interventions, such as disease state management programs and medication therapy management (MTM) programs, have been initiated in an attempt to improve adherence to medications. One such program, Lucas County MTM program is sponsored by an employer group and provides services to Lucas County employees diagnosed with diabetes, hypertension, and hyperlipidemia. The purpose of this study was to evaluate patient adherence to chronic disease medications and to determine the effect of adherence on the clinical outcomes of patients enrolled in Toledo Lucas County MTM program. This was a retrospective, longitudinal study. Data was obtained for 272 patients from The Pharmacy Counter prescription database. Medication adherence was measured using Medication Possession Ratio (MPR). Pearson correlation was used to determine the relationship between medication adherence and desired clinical outcomes. Multiple linear regression was used to determine if medication adherence is a predictor of clinical outcomes. Data analysis was performed using SPSS version16.0 and Microsoft Excel. Pearson correlation results indicated that MPR to diabetic medications was significantly correlated with age (r=0.387, p=0.000) and gender (r=-0.167, p=0.021). Further, age was significantly correlated with gender (r=-0.148, p=.042) and number of diseases (r=0.278, p=0.000) among diabetic patients. However, there were no significant predictors of change in A1c among diabetic patients. Among hypertension patients, change in systolic blood pressure was significantly correlated with change in diastolic blood pressure (r=0.553, p=0.000), gender (r=0.134 p=0.024), co-pay (r=0.118, p=0.048), and number of diseases (r=-0.132, p=0.026). Further, change in diastolic blood pressure was significantly correlated with MPR (r=-0.178, p=0.003). MPR was also found to be significantly correlated with gender (r=-0.138, p=0.020, co-pay (r=0.141, p=0.018), and number of diseases (r=0.139, p=0.019). Regression model for hypertension patients indicated that number of diseases (β = -0.130, p = 0.01), and change in diastolic blood pressure (β = 0.550, p = 0.000) were significant predictors of change in systolic blood pressure. Further, MPR (β = -0.151, p = 0.003) and change in systolic blood pressure (β = 0.552, p = 0.000) were found to be significant predictors of change in diastolic blood pressure. Thus, patients enrolled in the Lucas County MTM program showed high average adherence to hypertension medications. This study also identified predictors of clinical outcomes associated with diabetes and hypertension. Advisors/Committee Members: Pinto, Sharrel.

▼ Background: Studies have shown that racial and ethnic disparities in healthcare among adults with diabetes persist even after controlling for demographic and socioeconomic factors. To eliminate healthcare disparities in the U.S., monitoring and reporting the most recent trends of disparities are critically important. In addition, no studies were found in the literature that focused on disparities in timeliness and patient centeredness of health care using retrospective databases.Objectives: To examine the most recent racial and ethnic disparities in quality of health care (receipt of diabetes services, timeliness, and patient centeredness) among adults with diabetes in the U.S. Methods: The 2005 and 2006 Medical Expenditure Panel Survey (MEPS) data files including the Diabetes Care Survey and the Self-Administered Questionnaire were used. The racial and ethnic disparities in receipt of recommended diabetes services, timeliness, and patient centeredness were examined. Statistical analyses included the chi-square test and logistic regression to evaluate the disparities before and after controlling for the confounding factors (age, gender, family income, education, health insurance coverage, residential location, and language spoken most often at home). Results: In 2005–2006, the racial and ethnic disparities in quality of health care among U.S. adults with diabetes still exist. Blacks and Hispanics were less likely to receive recommended diabetes services and patient-centered health care than white Americans. The only exception was in regard to foot examinations. There was no statistically significant difference in timeliness of health care among racial and ethnic groups. Conclusions: Racial and ethnic disparities in receipt of recommended diabetes services and patient centeredness of health care among adults with diabetes remained in the U.S. in 2005–2006. Age, family income, health insurance coverage, education, residential location, and English-speaking were correlated with racial and ethnic disparities. As this study focused on disparities among Whites, Blacks and Hispanics, future studies comparing possible differences among other U.S. racial groups are needed. Advisors/Committee Members: Holiday-Goodman, Monica.