Biological disease-modifying anti-rheumatic drugs (DMARDs) for the treatment of Rheumatoid Arthritis, particularly TNF-α inhibitors, have been shown to improve patient outcome by slowing or halting radiographic damage. However, similar to most immunemodulators, there is an increased risk of infections co-incident with Tumour necrosis factor (TNF)-α inhibitor use, particularly the risk of activated latent tuberculosis infection (LTBI). Therefore, local and international guidelines recommend pre-screening for tuberculosis (TB) prior to the initiation of TNF-α therapy in rheumatoid arthritis (RA) patients. Also of critical importance in South Africa is the need for clinicians to be aware of environmental risk factors such as TB being highly endemic. Thus, a qualitative analysis was performed to investigate rheumatologists’ perceptions of TB co-incident with TNF-α inhibitors. Method: Physicians (n=18) practising rheumatology in the private and public healthcare sectors in Gauteng were interviewed to obtain their perceptions and attitudes related to TB co-incident with TNF-α inhibitor use. Interviews were audio-recorded and the transcripts analysed using thematic content analysis. Results: The determinants of health equity: Affordability, accessibility and availability of medicines (specifically TNF-α inhibitors) was reported to be different for the public care versus the private care patient. The high cost of TNF-α inhibitors warranted funding predominantly by the private medical schemes. A higher occurrence of latent TB infection was reported by physicians practising in the public or combined practice compared to the occurrence of LTBI in the private sector (21.4%versus 1.5%). The majority of study participants advocated pre-screening of TB, prior to the initiation of TNF-α inhibitors, in RA. However, it was suggested that because of the high occurrence of LTBI in the public sector, Isoniazid preventative therapy (IPT) should be compulsory, irrespective of the patient’s TB status, for the duration of TNF-α therapy. Most study participants supported local South African Rheumatism and Arthritis Association (SARAA) guideline recommendation to re-screen for TB by chest x-ray (CXR), every 6 months. However, the value of re-screening using diagnostic tools, purified protein derivative (PPD) skin test or interferon-gamma release assays (IGRAs) was queried due to the possibility of false readings. The occurrence of associated active TB in RA patients on TNF-α inhibitors was reported to be 0.07% in the private or combined practice versus 3.00% in the public sector. Forty percent of TB cases were reported to be extra-pulmonary. Despite active vigilance, some physicians reported that active TB month occurred months after the cessation of TNF-α inhibitor therapy. [Similar findings were observed from the British Society for Rheumatology Biologics Register (BSRBR)]. The majority of patients that developed TB co-incident with TNF-α inhibitors were treated successfully with TB chemotherapy. Only 1 of 12 patients died of extra-pulmonary TB, following compassionate use of infliximab in public care. Conclusion: Physicians practising rheumatology in Gauteng were of the opinion that there is a TB risk associated with the use of TNF-α inhibitors for the management of rheumatoid arthritis, as South Africa is a TB endemic country. Most acknowledged that these biological DMARDs were efficacious in slowing or halting radiographic progression in rheumatoid arthritis, but emphasised the need to take steps to prevent TB reactivation in the immuno - compromised RA patients and to remain overtly vigilant for active TB. In clinical practice, physicians mentioned that the monitoring and management of TB associated with TNF-α inhibitors appears to follow the socio-economic status of the RA patient and that distinct recommendations should be made for the public healthcare as well as the private healthcare sectors. Different opinions emanated from different physicians relating to the adequacy of local SARAA guidelines for the prevention of TB associated with TNF-α inhibitors. Some physicians mentioned that local guidelines were sufficient, whilst other physicians mentioned that the diagnostic tools were inadequate in the South African setting and that additional precautions should be taken in the form of IPT for the full duration of TNF-α therapy for all candidates, irrespective of TB status determined during pre-screening. As the science of biological DMARDs evolves with the rapid development of new medicinal therapies, physicians showed a preference to consider alternative non TNF-α biological DMARDs that had a lower risk of associated TB, specifically in high-risk RA patients. Physicians’ overall perception of the management of RA with TNF-α inhibitor therapy was that the risk-benefit assessment of these interventions, as well as patient preference and economic considerations should be taken into account.

A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, in fulfilment of the requirements for the degree of Master of Pharmacy / 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. / MT2017

Wan Pui Chu Christina. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2004. / Includes bibliographical references (leaves 167-191). / Abstracts in English and Chinese. / PUBLICATIONS BASED ON WORK IN THIS THESIS --- p.i / ABSTRACT --- p.ii / ACKNOWLEDGEMENT --- p.vii / TABLE OF CONTENTS --- p.viii / Chapter CHAPTER 1 --- INTRODUCTION --- p.1 / Chapter 1.1 --- Introduction to the Vanilloid Receptor --- p.1 / Chapter 1.1.1 --- Properties of the VR1 Channel --- p.2 / Chapter 1.1.2 --- Explaining the Unexplained: De sensitization and Pungency --- p.6 / Chapter 1.2 --- The Quest for the Endogenous Ligand: Activation versus Modulation --- p.2 / Chapter 1.2.1 --- Anandamide and the Cannabinoid System --- p.12 / Chapter 1.2.2 --- Inflammatory Mediators and Lipid Metabolites --- p.15 / Chapter 1.3 --- The Variegated Vanilloid Receptor: Multiple Actions of TRPV1 --- p.18 / Chapter 1.3.1 --- Vanilloid-induced Hypothermia: some like it cold --- p.18 / Chapter 1.3.2 --- "Three's a crowd: Vanilloids, Substance P, and the Emetic Reflex" --- p.22 / Chapter 1.3.3 --- Grooming Behavior and Locomotor Changes: Further Involvement of Neurokinins? --- p.29 / Chapter 1.4 --- Aims and Objectives of the Present Study --- p.33 / Chapter CHAPTER 2 --- METHODS --- p.39 / Chapter 2.1 --- Animals --- p.39 / Chapter 2.2 --- Stereotaxic Surgery and Transmitter Implantation --- p.39 / Chapter 2.3 --- Measurement of Emesis and Genital Grooming --- p.41 / Chapter 2.4 --- Measurement of Locomotor Activity and Body Temperature --- p.41 / Chapter 2.5 --- Experimental Procedures for Central Injection Studies --- p.45 / Chapter 2.6 --- Experimental Procedures for Peripheral Injection Studies --- p.47 / Chapter 2.7 --- Drug Formulation --- p.48 / Chapter 2.8 --- Statistical Analysis --- p.49 / Chapter CHAPTER 3 --- RESULTS --- p.51 / Chapter 3.1 --- Actions of Intracerebroventricularly Administered Vanilloid Agonists --- p.51 / Chapter 3.1.1 --- General Behaviour --- p.51 / Chapter 3.1.2 --- Emetic Action of Vanilloids --- p.52 / Chapter 3.1.3 --- Anti-Emetic action of Vanilloids against Copper Sulphate --- p.55 / Chapter 3.1.4 --- Vanilloid-induced Hypothermia --- p.58 / Chapter 3.1.5 --- RTX-induced Genital Grooming --- p.65 / Chapter 3.1.6 --- Effects of Vanilloids on Locomotor Activity --- p.67 / Chapter 3.1.7 --- Summary of Central Agonist Studies --- p.76 / Chapter 3.2 --- Effects of Intracerebroventricularly Administered Capsazepine on Vanilloid-induced Responses --- p.78 / Chapter 3.2.1 --- Effect of Capsazepine on Vanilloid-induced Emesis --- p.78 / Chapter 3.2.2 --- Effect of Capsazepine on the Anti-Emetic Action of Vanilloids --- p.82 / Chapter 3.2.3 --- Effect of Capsazepine on Vanilloid-induced Hypothermia --- p.84 / Chapter 3.2.4 --- Effect of Capsazepine on RTX-induced Genital Grooming --- p.88 / Chapter 3.2.5 --- Effect of Capsazepine on Locomotor Activity of Vanilloid-treated Animals --- p.90 / Chapter 3.3 --- "Peripheral Studies with RTX，,Capsazepine, and Ruthenium Red" --- p.93 / Chapter 3.1.1 --- Experiment 1: Actions of Resiniferatoxin --- p.93 / Chapter 3.1.2 --- Experiment 2: Effects of Capsazepine and Ruthenium Red administered alone --- p.99 / Chapter 3.1.3 --- Experiment 3: Effects of Capsazepine and Ruthenium Red on RTX- induced Responses --- p.104 / Chapter CHAPTER 4 --- DISCUSSION --- p.113 / Chapter 4.1 --- General Considerations --- p.113 / Chapter 4.2 --- Emetic Action of Vanilloids --- p.116 / Chapter 4.3 --- Anti-Emetic Action of Vanilloids --- p.124 / Chapter 4.4 --- Hypothermic Action of Vanilloids --- p.133 / Chapter 4.5 --- Resiniferatoxin-induced Genital Grooming --- p.147 / Chapter 4.6 --- Actions of Capsazepine and Ruthenium Red --- p.152 / Chapter 4.7 --- Locomotor Activity --- p.157 / Chapter CHAPTER 5 --- SUMMARY --- p.162 / REFERENCES --- p.167

Dissertation (Ph.D.) -- University of Texas Southwestern Medical Center at Dallas, 2006. / Vita. Bibliography: p.97-109

The pharmacokinetics of orally administered ranitidine were studied in 10 patients with endoscopically proved duodenal ulceration after a single 150 mg dose and after 4 weeks 1 ranitidine treatment (150 mg twice daily), at which time there was endoscopic evidence of complete ulcer healing. After a single dose the median elimination half-life was 135 minutes and the median area under the curve (AUC) was l 844 ng/ml.hr. Although the maximum concentration after a single dose (Cmax = 365 ng/ml) was significantly different from that after continuous treatment (Cmax = 562 ng/ml) (p <0,05) there was no significant difference between the minimum concentrations at 12 hours post-dosing (Cmin = 35 ng/ml and 30 ng/ml respectively) and the median half-lives were identical. No accumulation of ranitidine occurred in these patients after 4 weeks' chronic ranitidine treatment. Five patients received 20 mg ranitidine intravenously. The apparent volume of distribution of the central compartment ranged from 10,5 to 28,4 1 while the elimination rate constant β range from 0,34 to 0,78 h⁻¹ with the t½ ranging from 53 to 122 minutes. The mean oral bioavailability was 51%. The pharmacokinetics of ranitidine were studied in a further 7 patients with chronic duodenal ulceration who showed endoscopic evidence of unhealed ulcers after at least 8 weeks' treatment with ranitidine. There were no significant differences in any of the pharmacokinetic parameters when these patients were compared with the 10 responders above after multiple-dosage except that the disposition rate constant was smaller in non-responders (0,24 h⁻¹ compared with 0,31 h⁻¹, p <0,002). Two patients did, however, have very low plasma concentrations with above average basal and maximal acid output which may have contributed to the lack of response to ranitidine treatment. Single- and multiple-dose pharmacokinetic studies of oral ranitidine were carried out in 6 patients with chronic renal failure (RF) (creatinine clearance <25 ml/min) and compared with those obtained for the 10 patients with chronic duodenal ulceration with normal renal function (creatinine clearance >65 ml/min). There appeared to be no significant differences in absorption rate or amount absorbed but the median elimination rate constant was significantly reduced from 0,31 h⁻¹ in controls to 0,14 h⁻¹ in RF (p <0,002) resulting in a two-fold increase in t½ (312 minutes) after a single dose. Cmax did not differ significantly although Cmin and AUC were significantly larger in RF patients (both p <0,002). It is suggested that the dosage of ranitidine be reduced from 150 mg to 75 mg twice daily in severe renal failure although it was not possible to relate half-life, elimination rate constant or AUC directly to creatinine clearance.

Original published work submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Doctorate of Philosophy in Virology. Johannesburg 2017. / Introduction: HIV-infected and HIV-exposed-uninfected children have a heightened susceptibility to some vaccine preventable disease. There is a paucity of data on immunogenicity of vaccines in these children, including HIV-infected children who are initiated on early antiretroviral therapy (ART). We evaluated the effect of maternal HIV-exposure and timing of ART in HIV-infected children on antibody responses to combined diphtheria-toxoid (DT) -tetanus-toxoid (TT)-whole cell pertussis (wP) and Haemophilus influenzae type b conjugate vaccine (HibCV); monovalent hepatitis B vaccine (HepB) and live-attenuated measles vaccine (MV). Methods: Samples obtained from children aged 6–12 weeks who had been enrolled into the CIPRA-SA study were analysed. Briefly, HIV-uninfected children born to HIV-uninfected (HIV-unexposed) and HIV-infected mothers (HEU). Additionally, we enrolled perinatally HIV-infected children with CD4+%≥25% randomized to deferred-ART (i.e. initiated when clinically or immunologically indicated per the then WHO recommended treatment criteria; ART-Def) or immediate-ART initiation (i.e. initiated on ART immediately upon confirmation of HIV-infection status at 4-10 weeks of age; ART-Immed). Children enrolled in the ART-Immed arm were further randomized to interrupt ART at one-year (ART/12m) or two-years of age (ART/24m). Additionally, a convenience sample of HIV-infected children with CD4+<25% initiated on immediate-ART was enrolled (ART-CD4+<25%). Children received a primary series of DTwP-HibCV/HepB at 6, 10 and 14 weeks of age; and MV at 40 weeks of age. Booster dose of DTwP and MV was given at 15-18 months of age. Sampling time-points were: prior to the first dose of vaccine, four weeks after the third dose (18 weeks age), 24 weeks after the third dose (39.3 weeks of age), at the time of the booster dose (15- 18 months age), two to four weeks after the booster dose and at 24 months of age. Samples were analysed for antibodies for DT, TT, PT, FHA, HepB measured by Luminex microbead-immunoassay; and MV antibodies were quantified by an indirect enzyme immunoassay. Results: Antibody kinetics and response to primary series of DTwP-HibCV/HepB: Pre-vaccination GMCs were higher in HIV-unexposed than HEU children for TT, but lower for HepB, DT and FHA. Post-vaccination, sero-conversion, sero-protection and GMCs were similar in HEU and HIV-unexposed children for all vaccines. Furthermore, GMCs were higher in HIV-unexposed for TT, DT, HepB and FHA than in ART-Immed children; and for TT, HepB and PT than in ART-Def children. Nevertheless, there was no difference in proportion of HIV-unexposed and HIV-infected children who developed sero-protective vaccine-specific antibody levels post-vaccination. The timing of ART initiation generally did not affect immune responses to vaccines between HIV-infected groups. Antibody kinetics and booster responses to DTwP-HibCV/HepB vaccines: Pre-booster GMCs were generally higher in HIV-unexposed than HIV-infected children for all vaccine epitopes. Post-booster and at 24 months of age the ART-Def group had lower GMCs (except to FHA), and were less likely to have sero-protective antibody levels compared to HIV-unexposed group. Also, post-booster and at 24 months of age, GMC were generally higher in HIV-unexposed than ART-Immed children, and a higher percentage of HIV-unexposed than ART-Immed children maintained antibody levels ≥1IU/ml to TT and DT at 24 months of age. The GMCs and percentage of children with sero-protective thresholds were similar pre-booster and at 24 months of age between HIV-unexposed and HEU children. Antibody kinetics and response to measles virus vaccine: At 7.3 weeks of age, the proportion with sero-protective titers was higher in HIV-unexposed (65.2%) compared to any HIV-infected group (range: 16.7% to 41.8%); but dropped to <17% in all Groups at age 19.6 weeks. Twenty-eight weeks following the first measles-vaccine, ART/12m were less likely to have sero-protective titers (79.3%) compared to HIV-unexposed (94.8%; p<0.001), ART-Def (95.7%; p=0.003) or ART/24m (92.1%; p=0.02). Although the proportion with sero-protective levels were similar between groups immediately post-booster dose, this was lower in HEU (79.6%; p=0.002) and ART/12m (80.3%; p=0.01) compared to HIV-unexposed (94.3%) 41-weeks later. Conclusion: Primary vaccination with DTwP-HibCV/HBV of HIV-infected children initiated on early-ART confers similar immunity compared to HIV-unexposed children. HIV-infected children had poor anamnestic responses, if ART was not initiated prior to primary vaccination. In contrast, the memory response and persistence of antibody to most vaccine epitopes were similar between HIV-unexposed and HEU children. Increased waning of vaccine induced immunity over a 24 month period in ART-Def, ART/12m and HEU children following MV booster-dose; indicating the need for further booster doses after two-years of age in these children. I recommend close monitoring of HEU children, as this group makes up most children born to HIV-infected mothers and what facets of the immune system have been impacted by maternal exposure to HIV. / MT2017

No description available.

by Koo Po Lan. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2001. / Includes bibliographical references (leaves 120-130). / Abstracts in English and Chinese. / Acknowledgement --- p.i / Abstract --- p.ii / Abstract (Chinese version) --- p.iv / Content --- p.vii / List of Abbreviations --- p.xi / List of Figures and Tables --- p.xiii / Chapter Chapter 1 --- Introduction / Chapter 1.1 --- Saponins --- p.1 / Chapter 1.2 --- Structure of Saponin --- p.2 / Chapter 1.2.1 --- Triterpene Class --- p.2 / Chapter 1.2.2 --- Steroid Class --- p.3 / Chapter 1.2.2.1 --- Spirostanol Glycoside --- p.4 / Chapter 1.2.2.2 --- Furostanol Glycoside --- p.4 / Chapter 1.2.3 --- Steroid Alkaloid Class --- p.5 / Chapter 1.3 --- Steroidal Saponin as Anti-Tumor Drug --- p.5 / Chapter 1.4 --- Possible Anti-Tumor Action Mechanisms of Steroid Saponin --- p.6 / Chapter 1.4.1 --- Direct Cytotoxic and Growth Inhibitory Effects --- p.7 / Chapter 1.4.2 --- Immune-Modulatory Effects --- p.8 / Chapter 1.5 --- Possible Anti-Carcinogenicity Action Mechanism of Saponin --- p.9 / Chapter 1.5.1 --- Saponin Binding to Bile Acids --- p.9 / Chapter 1.6 --- Saponin as Cardioactive Drug --- p.9 / Chapter 1.7 --- Liver Cancer --- p.10 / Chapter 1.7.1 --- Prevalence of Hepatocellular Carcinoma (HCC) --- p.11 / Chapter 1.8 --- Coronary Heart Disease (CHD) --- p.12 / Chapter 1.8.1 --- Prevalence and Risk Factors of CHD --- p.12 / Chapter 1.9 --- Diosgenin --- p.14 / Chapter 1.10 --- Hong Kong (HK) Products --- p.15 / Chapter 1.10.1 --- HK-18 (Polyphyllin D) --- p.15 / Chapter 1.11 --- DI AO XIN XUE KANG (DI AO) --- p.17 / Chapter 1.12 --- Aims of My Project --- p.20 / Chapter 1.12.1 --- In Vitro Study of the Effect of HK-18 on Human Hepatocellular Carcinoma Cell Line (HepG2) --- p.21 / Chapter 1.12.2 --- In Vivo Study of the Effect of HK-18 by Human Liver Tumor HepG2 Cells-Bearing Nude Mice Model --- p.21 / Chapter 1.12.3 --- In Vitro Study of the Effect of HK-18 on Multidrug- Resistant Human Hepatocellular Carcinoma Cell Line (R-HepG2) --- p.22 / Chapter 1.12.4 --- Myocardial Ischemia-Reperfusion (IR) Injury in Isolated- Perfused Rat Heart Model --- p.23 / Chapter 1.12.5 --- Effect of DI AO Pretreatment on Global IR Injury --- p.26 / Chapter 1.12.6 --- Effect of DI AO Pretreatment on Isoproterenol-Induced Myocardial Injury in Rats --- p.26 / Chapter Chapter 2 --- Materials and Methods / Chapter 2.1 --- Materials --- p.28 / Chapter 2.1.1 --- Cell Lines and Culture Medium / Chapter 2.1.1.1 --- Cell Lines --- p.28 / Chapter 2.1.1.2 --- Culture Medium --- p.29 / Chapter 2.1.2 --- Chemicals --- p.30 / Chapter 2.1.3 --- Buffers and Reagents --- p.31 / Chapter 2.2 --- Methods / Chapter 2.2.1 --- In Vitro Studies --- p.33 / Chapter 2.2.1.1 --- In Vitro Cytotoxicity --- p.33 / Chapter 2.2.1.2 --- Cell Cycle Analysis by Flow Cytometry --- p.34 / Chapter 2.2.1.3 --- Maintenance of P-glycoprotein in R-HepG2 cells by Doxorubicin and HK-18 --- p.35 / Chapter 2.2.1.4 --- Assessment of DNA Fragmentation --- p.36 / Chapter 2.2.2 --- In Vivo Assessment of the Anti-Tumor Activity of HK-18 --- p.37 / Chapter 2.2.2.1 --- Animals and Tumor Inoculation --- p.37 / Chapter 2.2.2.2 --- Drug Administration --- p.37 / Chapter 2.2.2.3 --- Assessment of the Tumor Size and Tumor Weight --- p.38 / Chapter 2.2.2.4 --- Plasma Preparation --- p.38 / Chapter 2.2.2.5 --- Measurement of the Plasma Enzyme Activity --- p.39 / Chapter 2.2.3 --- Isoproterenol (ISO)-Induced Myocardial Injury (Rat Model) --- p.40 / Chapter 2.2.3.1 --- Animals --- p.40 / Chapter 2.2.3.2 --- Drug Preparations --- p.40 / Chapter 2.2.3.3 --- Animal Treatment --- p.41 / Chapter 2.2.3.4 --- Preparation of Myocardial Tissue Homogenate --- p.41 / Chapter 2.2.3.5 --- Preparation of Cytosolic Fraction of Heart Homogenates --- p.42 / Chapter 2.2.3.6 --- Myocardial Antioxidant Enzyme Activity --- p.42 / Chapter 2.2.3.6.1 --- Glutathione Reductase (GRD) --- p.42 / Chapter 2.2.3.6.2 --- Glutathione S-Transferases (GST) --- p.43 / Chapter 2.2.3.7 --- Myocardial Antioxidant Capacity --- p.43 / Chapter 2.2.3.7.1 --- Myocardial Malondialdehyde (MDA) Content --- p.43 / Chapter 2.2.3.7.2 --- Myocardial Thiol Content --- p.44 / Chapter 2.2.3.7.3 --- Tert-Butylhydroperoxide (tBHP)-Induced Thiol Depletion --- p.45 / Chapter 2.2.3.7.4 --- TBHP-Induced Thiobarbituric Acid-Reactive Substances (TBARS) Formation --- p.45 / Chapter 2.2.4 --- Myocardial Ischemia-Reperfusion (IR) Injury --- p.46 / Chapter 2.2.4.1 --- Langendorff Isolated Perfused Rat Heart --- p.46 / Chapter 2.2.4.1.1 --- Preparation of Perfusion Buffer --- p.46 / Chapter 2.2.4.1.2 --- Preparation of Isolated Rat Heart --- p.47 / Chapter 2.2.4.1.3 --- Myocardial Global Ischemia-Reperfusion Injury --- p.49 / Chapter 2.2.4.1.4 --- Contractile Force Recovery --- p.49 / Chapter 2.2.5 --- Statistical Analysis --- p.50 / Chapter Chapter 3 --- Study of HK-18 on Anti-Tumor Effect / Chapter 3.1 --- In Vitro Study of HK-18 on Human Hepatoma Carcinoma Cell Line (HepG2) --- p.51 / Chapter 3.1.1 --- The Effect of HK-18 on Cell Proliferation of HepG2 Cells by MTT Assay --- p.52 / Chapter 3.1.2 --- DNA Fragmentation Assay --- p.54 / Chapter 3.1.3 --- The Effect of HK-18 on Cell Cycle Phase Distribution --- p.57 / Chapter 3.2 --- In Vivo Study of HK-18 on HepG2-Inoculated Nude Mice --- p.61 / Chapter 3.2.1 --- Assessment of the Anti-Tumor Activity of HK-18 --- p.61 / Chapter 3.2.2 --- The Effect of HK-18 Towards Heart Tissue --- p.65 / Chapter 3.2.3 --- In Vitro Study of HK-18 on Multidrug Resistant Cell Line (R-HepG2) --- p.68 / Chapter 3.2.4 --- The Comparison of the Cytotoxicity of DOX on the Parental Cells and Resistant Cells of HepG2 --- p.69 / Chapter 3.2.5 --- The Effect of HK-18 on Cell Proliferation of R-HepG2 Cells by MTT Assay --- p.72 / Chapter 3.2.6 --- DNA Fragmentation Assay --- p.74 / Chapter 3.2.7 --- The Effect of HK-18 on Cell Cycle Phase Distribution --- p.77 / Chapter 3.2.8 --- The Relationship Between HK-18 and P-glycoprotein --- p.80 / Chapter Chapter 4 --- Study of the Cardioprotective Effect of DI AO / Chapter 4.1 --- Myocardial Ischemia-Reperfusion (IR) Injury in Isolated- Perfused Rat Heart --- p.82 / Chapter 4.1.1 --- Time Course of Global Ischemia-Reperfusion-Induced LDH Leakage --- p.82 / Chapter 4.1.2 --- Effect of DI AO Pretreatment on Global IR Injury --- p.85 / Chapter 4.1.2.1 --- LDH Leakage --- p.85 / Chapter 4.1.2.2 --- Contractile Force --- p.87 / Chapter 4.2 --- Isoproterenol-Induced Myocardial Injury in Rats --- p.89 / Chapter 4.2.1 --- Effect of DI AO Pretreatment --- p.89 / Chapter 4.2.2 --- Alternations in the Activity of Myocardial Antioxidant Enzymes --- p.91 / Chapter 4.2.3 --- Alternations in Myocardial Antioxidant Capacity --- p.94 / Chapter Chapter 5 --- Discussion / Chapter 5.1 --- The Significance of the Study of Saponin in the Treatment of Liver Cancer and Heart Injury --- p.96 / Chapter 5.2 --- Effect of HK-18 on Human Hepatocellular Carcinoma Cell --- p.101 / Chapter 5.3 --- Mechanism Study of Anti-Tumor Effect of HK-18 --- p.102 / Chapter 5.4 --- Cytotoxicity of HK-18 Toward Normal Tissue --- p.105 / Chapter 5.5 --- Effect of HK-18 on Multidrug Resistant Human Hepatocellular Carcinoma / Chapter 5.6 --- Protective Effect of DI AO Against Isoproterenol (ISO)- Induced Myocardial Injury --- p.110 / Chapter 5.7 --- Cardioprotective Effect of DI AO Against Ischemia- Reperfusion (IR) Injury --- p.111 / Chapter 5.8 --- Effect of DI AO Pretreatment on Myocardial Antioxidant Enzymes Activities and Antioxidant Capacity --- p.113 / Chapter 5.9 --- Conclusion and Future Prospect --- p.117 / Chapter Chapter 6 --- References --- p.121

A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, in fulfilment of the requirements for the degree of Doctor of Philosophy Department of Pharmacy and Pharmacology, Faculty of Health Sciences, University of the Witwatersrand, South Africa Department of Pharmacy and Pharmacology, Faculty of Health Sciences, University of the Witwatersrand, South Africa Johannesburg 2017. / 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. / MT2017

Thesis (M.Pharm.)--University of the Witwatersrand, Faculty of Health Sciences, 2013. / Sexually transmitted infections (STIs) are a global concern and more specifically southern Africa has seen a tremendous upsurge in infection rates. KwaZulu-Natal is the province found to have the highest Human Immunodeficiency Virus and STI infection rates. From an ethnobotanical study conducted specifically in northern Maputaland (Mabibi, Tshongwe, Mseleni and Mbazwana), it was found that the lay people most often used plants in various combinations for the treatment of STI related symptoms. The use of these plant combinations were thus antimicrobially investigated and the toxicity properties determined. The dichloromethane: methanol (organic) and aqueous extracts were prepared for each plant in situ using collected ground dried plant material. The plants (individually and in combination) were investigated for toxic potential using the 3-[4,5-dimethyl-2-thiazol-yl]-2,5-diphenyl-2H-tetrazolium bromide (MTT) cellular viability assay on the human kidney epithelial (Graham) cell line. The antimicrobial activities for each sample, as well as for each combination, were then further investigated using the minimum inhibitory concentration (MIC) assay. The six STI pathogens investigated in this study were Candida albicans (ATCC 10321), Ureaplasma urealyticum (clinical strain), Oligella ureolytica (ATCC 43534), Gardnerella vaginalis (ATCC 14018), Trichomonas vaginalis (clinical strain) and Neisseria gonnorhoeae (ATCC 19424).