3. Electronic Theses and Dissertations (ETDs) - All submissions

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    Nanovectors for targeted chemotherapy in cervical cancer
    (2017) Zardad, Az-Zamakhshariy
    Cervical Intraepithelial Neoplasia (CIN) or Human Papilloma Virus (HPV) is known as the precancerous stages of cervical cancer and may be treated with antineoplastic agents Current treatment includes intravenous administration of Gemcitabine and 5-Fluorouracil however, these drugs have an undesirable side effect profile. This may be overcome by local administration of chemotherapeutic drugs to the site of the cancer. The purpose of this study was to design a drug delivery system that can be locally administered to the site of the cervical cancer and possess thermosonic properties. Designs of three Thermosonic Injectable Organogels (TIO’s) were undertaken using ring opening polymerization (open ring reaction) to formulate three different gels to test the response ability of the gels against thermal and ultrasound exposure. The times taken for these gels to form were recorded at below 15 minutes. All three TIO’s responded differently to thermal and ultrasound stimuli. Physical changes in the gels were noted and further studies were undertaken to confirm their responsiveness towards the dual-stimuli. All three TIO’s showed a dense microstructure containing pores catering for the incorporation of drugs or drug-loaded carriers. Rheological studies showed that there was an increase in viscosity of the gels under increasing heat even though the response differed between TIO formulations. The gels were non-cytotoxic at distinct concentrations ranging between 6.1mg/ml-7.8mg/ml. Solid Lipid Nanospheres (SLN’s) were then designed which encapsulated the mode antineoplastic drug 5-Fluorouracil. The SLN’s were spherical in shape and had an acceptable poly dispersion index (PDI) which was below 0.7 after ultrasonication and filtration of prepared samples. The SLN’s were then incorporated by direct additition and dispersion into the TIO formulations before undertaking the open ring reaction to form Thermosonic Injectable Nano-Organogels (TINO’s). The TINO’s were analysed for its swelling and erosive properties. Results showed that the TINO’s posesses both swelling and erosive properties. Furthermore, the TINO’s underwent dissolution studies that involved thermal and thermal with ultrasound stimuli to test the drug release rate and the stimuli responsiveness of the TINO. Results of the SLN’s showed a very slow release rate whether exposed to a single (thermal) or both thermal and ultrasound stimuli, indicating that the addition of ultrasound stimuli did not alter the drug release from the SLN’s. However, the incorporation of the SLN’s into the TIO’s prolonged the release rate. Hence increasing the SLN concentration in the TIO’s reduced the response towards ultrasound stimuli. Therefore lower ratios of SLN:TIO provided superior responsiveness compared to higher concentrations of SLN:TIO. TIO 1 and TINO 2 released drug with thermal stimuli and higher drug release occurred with exposure to both thermal and ultrasound stimuli. These TINO’s in conjunction with ultrasound responsiveness may be used as a potential platform for the delivery of antineoplastics in treating cervical cancer.
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    Inflammation-responsive self-oscillating polymeric gel to enhance dermal delivery of Neo-Geometric copper nanoparticles
    (2017) Murugan, Karmani
    Psoriasis vulgaris is a chronic, hyper-proliferative skin condition which affects the patient’s quality of life. The treatment strategy involves long term use of drugs that maintain the condition, however; playing a pivotal negative role in patient compliance. A constructive development in the design of treatment addressing the disease should focus on the challenges faced by current designs. Hence, cellular internalization and trans-barrier transport of nanoparticles can be manipulated on the basis of the physicochemical and mechanical characteristics of nanoparticles to enhance the treatment options of the condition by reducing dosing and increasing the healing due to intracellular drug delivery. Dictating these characteristics allows for the control of the rate and extent of cellular uptake, as well as delivering the drug-loaded nanosystem intra-cellularly which is imperative for drugs that require a specific cellular level to exert their effects, as is with psoriasis. Additionally, physicochemical characteristics of the nanoparticles should be optimal for the nanosystem to bypass the natural restricting phenomena of the body and act therapeutically at the targeted site. Neo-geometric copper nanoparticles (CuNPs) in the biomedical application ascertained skin permeation and retention of the CuNPs as a drug delivery system. The approach to the use of the nanocrystal exploited the shape properties as a function of enhanced cellular uptake and the copper in the inflamed psoriatic environment acted as a cytotoxic agent against hyper-proliferating keratinocytes. A Self-Oscillating Polymeric Network (SOPN) served as a vehicle for the topical delivery of the geometric CuNPs in addition to its oscillating phenomenon to promote the permeation of the active nanoparticles across the rate limiting barrier of the skin, the stratum corneum. This twofold system adequately targets the key limitations in addressing psoriasis. A statistical experimental design comprising a full factorial model for the optimization of the geometric CuNPs and Box-Behnken design applied on the SOPN served as a refining factor to achieve stable, homogenous, geometric nanoparticles using a one-pot method for the systematic optimization of the geometric CuNPs. The optimization of the SOPN involved amplitude and duration of the oscillations, permeation kinetics and cytotoxicity. After optimization of the nano-shapes and oscillations of the SOPN, extensive ex vivo cellular internalization studies were conducted to elucidate the effect of geometric CuNPs on uptake rates; in addition to the vital toxicity assays to further understand the cellular effect of geometric CuNPs as a drug delivery system. Complementing the geometry analysis; volume, surface area, orientation to the cell membrane and colloidal stability were also addressed. The SOPN was also investigated ex vivo for its biocompatibility to determine the LD50 and permeation kinetics. The in vivo study probed the nanosystem embedded in the innovative SOPN to stimulate the permeation of the CuNPs across the stratum corneum of the induced psoriasiform-plaque in a BALB/c mouse model. The results confirmed an optimized CuNPs-loaded SOPN topical system with promising plaque thickness reduction when compared with a commercial gold standard in the treatment of the skin condition. This novel system can be safely used with less frequent, lower dosing and no odour, therefore promoting patient compliance.
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    Pharmacotherapy prescribing patterns in the treatment of bipolar disorder in an outpatient population at Tara hospital
    (2015) Holzapfel, Eleanor
    Introduction Pharmacotherapy is a key component in the management of bipolar disorder. Whilst one might aim for fewer agents, not all patients with bipolar disorder can be stabilized with monotherapy and combination treatment (polypharmacy) is increasingly used to manage patients in clinical practice. Mood stabilizers have traditionally been prescribed as monotherapy, however the use of atypical antipsychotic agents is seen in clinical practice with various such agents approved for such usage. Combination treatment with an antipsychotic, preferably an atypical antipsychotic together with a standard mood stabilizer is also noted in clinical practice as well as recommended by guidelines. Bipolar patients managed in a specialist psychiatric setting have a greater chance of being managed with polypharmacy than in a general practice setting. The use of polypharmacy may also be attributed to receiving treatment in an academic environment. This current study was based on the application of diagnostic criteria and principles of the Diagnostic and Statistical Manual of Mental Disorders version IV TR (DSM IV TR), published by the American Psychiatric Association and The International Classification of Diseases version 10 (ICD 10), published by the World Health Organisation. Aims The study aims to describe the range and frequency of medications used in the management of bipolar bisorder in a specific setting as well as describe the nature and frequency of monotherapy versus polypharmacy use. Hypothesis The study hypothesized that the majority of patients attending the specialist / academic psychiatric outpatient clinic at Tara Hospital would be prescribed polypharmacy and that antipsychotics (typical or atypical) would be prescribed in combination with standard mood stabilizers in the majority of cases. Method The study took the form of a retrospective patient file review. The clinical files were for patients attending the Tara Hospital psychiatric outpatient clinic. The files of every patient who attended the clinic at least once in 2009 were screened and included in the study where the recorded ICD 10 code corresponded with a bipolar disorder subtype or a single manic or hypomanic episode. Where the recording of the ICD 10 code was missing or incomplete further scrutiny of the clinical notes enabled the researcher to establish a diagnosis of bipolar disorder using the ICD 10 and/ or DSM IV TR diagnostic criteria and therefore include the patient file in the study. Other necessary information was obtained by reviewing clinical notes as well as the prescription written on the last patient visit for 2009. Results The study found that the majority of patients (93.8%) were prescribed polypharmacy, with 3.2 the mean number of psychotropic medications prescribed per patient. Lithium was prescribed in 34.3% of patients. Sodium valproate was prescribed in 37.1% of patients. Eighty three point eight percent (83.8%) of the patients were prescribed at least one standard mood stabilizer. The atypical antipsychotics (46.6%) were prescribed more frequently than the typical antipsychotics (16.5%). Lamotrigine (31.8%) was the preferred novel anticonvulsant and the selective serotonin reuptake inhibitors (SSRI’s) were the most commonly prescribed antidepressant (28.9%). Clonazepam (26.8%) was the most frequently prescribed benzodiazepine add-on. The use of combination treatment to manage bipolar disorder was the rule rather than the exception. There was however much variety in the combinations used with no particular combination being prescribed in the majority of patients. Forty seven percent (47%) of the combinations used included a standard mood stabilizer and a typical or atypical antipsychotic. Conclusion The current study provides preliminary data on the prescribing patterns in bipolar disorder in a specialist psychiatric clinic within an academic complex in South Africa. The findings are in keeping with international studies and highlights that polypharmacy and combination treatment in the management of bipolar disorder is the norm in such settings. There is a large variation in clinician practices and much variety seen in the combinations of medications used to treat bipolar disorder despite the availability and use of treatment guidelines. This is perhaps because bipolar disorder is such a complex disorder and that most of the treatment recommendations are based on limited data. Treatment guidelines have emerged in order to attempt to standardize treatment and provide clinicians with algorithms to utilize and apply research findings in daily clinical practice. Further study into the effective prescribing principles for bipolar disorder is necessary.
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