Indiana University-Purdue University Indianapolis (IUPUI) / Choroidal neovascularization (CNV) is the vision-threatening characteristic of wet age-related macular degeneration (AMD), a major cause of blindness affecting almost 2 million elderly Americans. The current approved treatments target the dominant angiogenic mediator, vascular endothelial growth factor (VEGF). However, repeated injections of anti-VEGF drugs can cause ocular and systemic side effects, and about 30% of wet AMD patients are non-responsive. There is thus an unmet need to develop VEGF-independent antiangiogenic molecules to complement or combine with existing medications. I studied SH-11037, a novel homoisoflavonoid with potent and selective antiangiogenic activity against human retinal endothelial cells. Intravitreal SH- 11037 dose-dependently suppressed angiogenesis in the laser-induced CNV (LCNV) mouse model. These effects were prominent as early as 7 days post-laser treatment as measured by a novel ellipsoid quantification method of optical coherence tomography images in vivo. A supratherapeutic dose of 100 μM SH- 11037 was not associated with signs of murine ocular toxicity, and did not interfere with pre-existing retinal vasculature or retinal function. SH-11037 synergized with anti-VEGF therapy in vitro and in vivo, suggesting a VEGFindependent mechanism. By photoaffinity pulldown, I identified soluble epoxide hydrolase (sEH) as an SH-11037-binding target. sEH is a key enzyme in ω-3 and ω-6 fatty acid metabolism. sEH levels were dramatically upregulated in retinal sections from L-CNV mice and a specific sEH inhibitor, t-AUCB, significantly suppressed L-CNV lesion volume. Additionally, SH-11037 inhibited sEH enzymatic activity in vitro and in vivo in L-CNV mice. Given the role of sEH in the metabolism of docosahexaenoic acids (DHA), inhibition of sEH using small molecules like SH-11037 would enhance ocular DHA levels, with beneficial antiangiogenic and anti-inflammatory effects. SH-11037 is thus a novel sEH inhibitor, which could make it an alternative or additive therapy to existing anti- VEGF drugs for treatment of neovascular diseases in the eye and other tissues.

Chemical substance abuse and dependence constitute an increasing international and national phenomenon. Individuals, groups and communities are at risk of the mental, biological, legal and environmental implications associated with substance dependence. Human sexual behaviour is no new phenomenon to be studied. Human beings experience sexual behaviour and gratification as important. Sexual behaviour is not vital for the survival of the individual but vital for survival of the species. Sexual behaviour in combination with chemical substance abuse might pose further dangers to a person or group. Sexual behaviour where persons engage in sexual actions when using or abusing chemical substances could construct certain positive functions for persons. Qualitative researchers are interested in discovering the meaning persons attach to experiences. In understanding the dynamics of the phenomenon, possible contributions to the human sciences could be made. Chemical substance abuse and dependency affect the individual, his/her family systems and the community. Depressants and stimulants change the chemical functioning of the human brain and the mental health of the user. Despite the harm caused to the dependent person, abuse of the chemical substance is continued. The substance has various functions that the biological and psychological person becomes dependent on. Sexual behaviour is inherent in human nature, but not chemical substance abuse. It is expected by the researcher that there might be certain function(s) served by chemical substances in the sexual behaviour of persons. A literature study on the topic on the function of chemical substances in the sexual behaviour of persons yielded unsatisfactory results. Little research was found with regard to the function of chemical substances in relation to people’s sexual behaviour. In response to this need the researcher embarked on a qualitative research journey to explore the function of the chemical substances within the context of an individual’s sexual behaviour and practices. Chemical substances have different functions and affect the sexual behaviour, functioning and experiences of the users of such substances. Six objectives were set with the aim of developing an in-depth understanding of the function of chemical substances in sexual behaviour. The research question of this investigation leads to a clear inquiry into the phenomenon that was examined and analysed and yielded useful new information. This qualitative research project is characterised by its inductive features, openness to change and interest in human behaviour. The study is characterised by an interpretive nature as an interpretative investigation. An effort was made towards understanding the phenomenon through observation and exploration. Persons were invited to participate in the research and reported themselves to the researcher, the process of self-selection sampling was utilised. In drawing a sample from the population of patients at a treatment centre an interactive approach to the process was followed by conducting semi-structured and in-depth interviews as a method of data collection. Data analysis and processing was executed according to the eight steps for qualitative data analysis as proposed by Tesch (in Creswell, 2009). Data verification for the assessment of the trustworthiness of the research findings was achieved by utilizing Guba’s model as espoused in Krefting (1991). Informed consent, confidentiality and management of information were some of the ethical considerations adhered to in the planning and execution of this research project. The nature of this study is marked by the person-centred approach in combination with the qualitative methodology and philosophy. The researcher found the two to be appropriate when a sensitive and private topic was to be explored. Participants were able to evaluate the meanings that were attached to their experiences within a psychologically sound environment. Themes became evident through the data analysis process. These themes were contrasted against a body of existing theory. The wholeness of human beings came to the fore and literature from a bio-neurological and humanistic perspective was found to be applicable. The social sciences and, in particular, social workers are concerned with the wellbeing of persons, their relevant systems and context. These dimensions of human beings were addressed by this study and aimed to contribute to further development in the science of psychotherapy and the understanding of the person within the phenomenon being studied. Therapists should be willing and demonstrate a sensitive ability to understand the client’s experiences from the person’s own point of view (Rogers, 1950: 444). In a relationship that is constructed for the purpose the aim should be mainly to understand the whole person (Rogers, 1952: 343). Therapists should develop an ability to see completely through the client’s eyes and adopt the person’s frame of reference. This is the basis for implementing “client-centred” therapy (Rogers 1950: 444). A key role of social work practice is facilitating the empowerment of persons, and their personal and interpersonal strengths according to their own self-determination (Zastrow, 2012:39); the researcher recommends a holistic full understanding of the person in his/her wholeness (Rogers, 1987: 486). / Exploring the functions of chemical substances in individuals' sexual behavior / Interviews in English and Afrikaans / Department of Social Work / M.A. (Social Work)

Chemical substance abuse and dependence constitute an increasing international and national phenomenon. Individuals, groups and communities are at risk of the mental, biological, legal and environmental implications associated with substance dependence. Human sexual behaviour is no new phenomenon to be studied. Human beings experience sexual behaviour and gratification as important. Sexual behaviour is not vital for the survival of the individual but vital for survival of the species. Sexual behaviour in combination with chemical substance abuse might pose further dangers to a person or group. Sexual behaviour where persons engage in sexual actions when using or abusing chemical substances could construct certain positive functions for persons. Qualitative researchers are interested in discovering the meaning persons attach to experiences. In understanding the dynamics of the phenomenon, possible contributions to the human sciences could be made. Chemical substance abuse and dependency affect the individual, his/her family systems and the community. Depressants and stimulants change the chemical functioning of the human brain and the mental health of the user. Despite the harm caused to the dependent person, abuse of the chemical substance is continued. The substance has various functions that the biological and psychological person becomes dependent on. Sexual behaviour is inherent in human nature, but not chemical substance abuse. It is expected by the researcher that there might be certain function(s) served by chemical substances in the sexual behaviour of persons. A literature study on the topic on the function of chemical substances in the sexual behaviour of persons yielded unsatisfactory results. Little research was found with regard to the function of chemical substances in relation to people’s sexual behaviour. In response to this need the researcher embarked on a qualitative research journey to explore the function of the chemical substances within the context of an individual’s sexual behaviour and practices. Chemical substances have different functions and affect the sexual behaviour, functioning and experiences of the users of such substances. Six objectives were set with the aim of developing an in-depth understanding of the function of chemical substances in sexual behaviour. The research question of this investigation leads to a clear inquiry into the phenomenon that was examined and analysed and yielded useful new information. This qualitative research project is characterised by its inductive features, openness to change and interest in human behaviour. The study is characterised by an interpretive nature as an interpretative investigation. An effort was made towards understanding the phenomenon through observation and exploration. Persons were invited to participate in the research and reported themselves to the researcher, the process of self-selection sampling was utilised. In drawing a sample from the population of patients at a treatment centre an interactive approach to the process was followed by conducting semi-structured and in-depth interviews as a method of data collection. Data analysis and processing was executed according to the eight steps for qualitative data analysis as proposed by Tesch (in Creswell, 2009). Data verification for the assessment of the trustworthiness of the research findings was achieved by utilizing Guba’s model as espoused in Krefting (1991). Informed consent, confidentiality and management of information were some of the ethical considerations adhered to in the planning and execution of this research project. The nature of this study is marked by the person-centred approach in combination with the qualitative methodology and philosophy. The researcher found the two to be appropriate when a sensitive and private topic was to be explored. Participants were able to evaluate the meanings that were attached to their experiences within a psychologically sound environment. Themes became evident through the data analysis process. These themes were contrasted against a body of existing theory. The wholeness of human beings came to the fore and literature from a bio-neurological and humanistic perspective was found to be applicable. The social sciences and, in particular, social workers are concerned with the wellbeing of persons, their relevant systems and context. These dimensions of human beings were addressed by this study and aimed to contribute to further development in the science of psychotherapy and the understanding of the person within the phenomenon being studied. Therapists should be willing and demonstrate a sensitive ability to understand the client’s experiences from the person’s own point of view (Rogers, 1950: 444). In a relationship that is constructed for the purpose the aim should be mainly to understand the whole person (Rogers, 1952: 343). Therapists should develop an ability to see completely through the client’s eyes and adopt the person’s frame of reference. This is the basis for implementing “client-centred” therapy (Rogers 1950: 444). A key role of social work practice is facilitating the empowerment of persons, and their personal and interpersonal strengths according to their own self-determination (Zastrow, 2012:39); the researcher recommends a holistic full understanding of the person in his/her wholeness (Rogers, 1987: 486). / Department of Social Work / M.A. (Social Work)

Indiana University-Purdue University Indianapolis (IUPUI) / Drug-drug interactions (DDIs) refer to situations where one drug affects the pharmacokinetics or pharmacodynamics of another. DDIs represent a major cause of morbidity and mortality. A common adverse drug reaction (ADR) that can result from, or be exacerbated by DDIs is drug-induced myopathy. Identifying DDIs and understanding their underlying mechanisms is key to the prevention of undesirable effects of DDIs and to efforts to optimize therapeutic outcomes. This dissertation is dedicated to identification of clinically important myopathic DDIs and to elucidation of their underlying mechanisms. Using data mined from the published cytochrome P450 (CYP) drug interaction literature, 13,197 drug pairs were predicted to potentially interact by pairing a substrate and an inhibitor of a major CYP isoform in humans. Prescribing data for these drug pairs and their associations with myopathy were then examined in a large electronic medical record database. The analyses identified fifteen drug pairs as DDIs significantly associated with an increased risk of myopathy. These significant myopathic DDIs involved clinically important drugs including alprazolam, chloroquine, duloxetine, hydroxychloroquine, loratadine, omeprazole, promethazine, quetiapine, risperidone, ropinirole, trazodone and simvastatin. Data from in vitro experiments indicated that the interaction between quetiapine and chloroquine (risk ratio, RR, 2.17, p-value 5.29E-05) may result from the inhibitory effects of quetiapine on chloroquine metabolism by cytochrome P450s (CYPs). The in vitro data also suggested that the interaction between simvastatin and loratadine (RR 1.6, p-value 4.75E-07) may result from synergistic toxicity of simvastatin and desloratadine, the major metabolite of loratadine, to muscle cells, and from the inhibitory effect of simvastatin acid, the active metabolite of simvastatin, on the hepatic uptake of desloratadine via OATP1B1/1B3. Our data not only identified unknown myopathic DDIs of clinical consequence, but also shed light on their underlying pharmacokinetic and pharmacodynamic mechanisms. More importantly, our approach exemplified a new strategy for identification and investigation of DDIs, one that combined literature mining using bioinformatic algorithms, ADR detection using a pharmacoepidemiologic design, and mechanistic studies employing in vitro experimental models.

Indiana University-Purdue University Indianapolis (IUPUI) / Traditional treatment strategy development for diseases involves the identification of target proteins related to disease states, and the interference of these proteins with drug molecules. Computational drug discovery and virtual screening from thousands of chemical compounds have accelerated this process. The thesis presents a comprehensive framework of computational drug discovery using system biology approaches. The thesis mainly consists of two parts: disease biomarker identification and disease treatment discoveries. The first part of the thesis focuses on the research in biomarker identification for human diseases in the post-genomic era with an emphasis in system biology approaches such as using the protein interaction networks. There are two major types of biomarkers: Diagnostic Biomarker is expected to detect a given type of disease in an individual with both high sensitivity and specificity; Predictive Biomarker serves to predict drug response before treatment is started. Both are essential before we even start seeking any treatment for the patients. In this part, we first studied how the coverage of the disease genes, the protein interaction quality, and gene ranking strategies can affect the identification of disease genes. Second, we addressed the challenge of constructing a central database to collect the system level data such as protein interaction, pathway, etc. Finally, we built case studies for biomarker identification for using dabetes as a case study. The second part of the thesis mainly addresses how to find treatments after disease identification. It specifically focuses on computational drug repositioning due to its low lost, few translational issues and other benefits. First, we described how to implement literature mining approaches to build the disease-protein-drug connectivity map and demonstrated its superior performances compared to other existing applications. Second, we presented a valuable drug-protein directionality database which filled the research gap of lacking alternatives for the experimental CMAP in computational drug discovery field. We also extended the correlation based ranking algorithms by including the underlying topology among proteins. Finally, we demonstrated how to study drug repositioning beyond genomic level and from one dimension to two dimensions with clinical side effect as prediction features.

Indiana University-Purdue University Indianapolis (IUPUI) / Aromatase inhibitors (AIs) are the current standard of care for the treatment of hormone receptor positive breast cancer in postmenopausal women. Nearly one-half of patients receiving AI therapy develop musculoskeletal toxicity that is characterized by joint and/or muscle pain and approximately one-fourth of patients discontinue their therapy as a result of musculoskeletal pain. Since there are no effective strategies for prevention or treatment, insight into the mechanisms of AI-induced pain is critical to improve treatment. However, there are few studies of AI effects in animal models of nociception. To determine whether AIs produce hypersensitivity in animal models of pain, I examined the effects of AI administration on mechanical, thermal, and chemical sensitivity in rats. The results demonstrate that (1) repeated injection of 5 mg/kg letrozole in male rats produces mechanical, but not thermal, hypersensitivity that extinguishes when drug dosing is stopped; (2) administering a single dose of 1 or 5 mg/kg letrozole in ovariectomized (OVX) rats also induces mechanical hypersensitivity, without altering thermal sensitivity and (3) a single dose of 5 mg/kg letrozole or daily dosing of letrozole or exemestane in male rats augments flinching behavior induced by intraplantar ATP injection. To determine whether the effects of AIs on nociceptive behaviors are mediated by activation or sensitization of peptidergic sensory neurons, I determined whether letrozole exposure alters release of calcitonin gene-related peptide (CGRP) from isolated rat sensory neurons and from sensory nerve endings in rat spinal cord slices. No changes in basal, capsaicin-evoked or high extracellular potassium-evoked CGRP release were observed in sensory neuronal cultures acutely or chronically exposed to letrozole. Furthermore, letrozole exposure did not alter the ability of ATP to augment CGRP release from sensory neurons in culture. Finally, chronic letrozole treatment did not augment neuropeptide release from spinal cord slices. Taken together, these results do not support altered release of this neuropeptide into the spinal cord as mediator of letrozole-induced mechanical hypersensitivity and suggest the involvement of other mechanisms. Results from this dissertation provide a new experimental model for AI-induced hypersensitivity that could be beneficial in delineating mechanisms mediating pain during AI therapy.

The use of methylenedioxymethamphetamine (MDMA) or Ecstasy is a phenomenon that has established itself in the widespread Rave culture. Ecstasy use causes not only physical, social and psychological problems in the development of the adolescent but may also influence his concentration and learning abilities. To prevent these problems educators should be well informed regarding current drug use trends and also be capable of assisting adolescents. Research regarding the nature of Ecstasy use and the characteristics of its users is lacking nationally. The increase in use amongst school going adolescents and young adults and the fact that there are side effects and unknown long term effects has made it imperative that educators learn as much as possible about this drug. The purpose of this research is therefore to furnish the educator with accurate information that will enable him to obtain a reference point from which assistance can be offered to the young Ecstasy user. / Psychology of Education / M.Ed.(Guidance and Counselling)

The use of methylenedioxymethamphetamine (MDMA) or Ecstasy is a phenomenon that has established itself in the widespread Rave culture. Ecstasy use causes not only physical, social and psychological problems in the development of the adolescent but may also influence his concentration and learning abilities. To prevent these problems educators should be well informed regarding current drug use trends and also be capable of assisting adolescents. Research regarding the nature of Ecstasy use and the characteristics of its users is lacking nationally. The increase in use amongst school going adolescents and young adults and the fact that there are side effects and unknown long term effects has made it imperative that educators learn as much as possible about this drug. The purpose of this research is therefore to furnish the educator with accurate information that will enable him to obtain a reference point from which assistance can be offered to the young Ecstasy user. / Psychology of Education / M.Ed.(Guidance and Counselling)