ETD Collection

Permanent URI for this collectionhttps://wiredspace.wits.ac.za/handle/10539/104


Please note: Digitised content is made available at the best possible quality range, taking into consideration file size and the condition of the original item. These restrictions may sometimes affect the quality of the final published item. For queries regarding content of ETD collection please contact IR specialists by email : IR specialists or Tel : 011 717 4652 / 1954

Follow the link below for important information about Electronic Theses and Dissertations (ETD)

Library Guide about ETD

Browse

Filters

2014 - 20182

Settings

Author: search.filters.author.Dangarembizi, Rachael

Search Results

Now showing 1 - 2 of 2
  • No Thumbnail Available
    Item
    A characterization and validation of the pyrogenic models and thermotric methids used for pharmacognostic evaluation of antipyretic medicine
    (2018) Dangarembizi, Rachael
    The development of safe and effective antipyretic and anti-inflammatory drugs remains an important focus of the pharmacological industry. Despite reports that rectal thermometry causes stress-induced hyperthermia in rodents, it remains the most commonly used method for measuring core body temperature during antipyretic drug-testing. The impact of the stressinduced hyperthermia on the accuracy and reliability of thermal responses reported in pharmacological studies investigating the efficacy of antipyretic drugs remains unclear. Additionally, the sickness response to Brewer’s yeast, the pyrogen recommended for inducing fever during antipyretic testing, remains largely uncharacterised and its mechanisms unknown. I used intra-abdominally implanted temperature-sensitive radiotelemeters to measure changes in the abdominal temperature of both normothermic and febrile rats injected with Brewer’s yeast, and exposed to rectal temperature measurement at hourly intervals for five hours. My results show that rectal temperature measurement is associated with a reproducible, nondecremental rise in abdominal temperature (0.6 - 0.8 °C) in normothermic rats. The hyperthermia was muted in febrile rats and was not blunted by the common habituation procedure. A comparison of temperatures measured using rectal thermometry with those measured using biotelemetry showed that rectal temperatures recorded using a thermocouple probe could be up to 0.5 °C lower or 0.7 °C greater than abdominal temperatures recorded using an abdominally implanted telemeter. The differences in thermal responses exhibited by normothermic vs febrile rats, coupled with the under- or overestimation of core body temperatures when one uses thermocouple probes supports my hypothesis that the procedure of rectal thermometry may affect the accuracy of thermal responses observed during antipyretic drug-testing. Having examined the methods used for temperature measurement, my second objective was to characterise the sickness response to the recommended and commonly used pyrogen for antipyretic screening; Saccharomyces cerevisiae (Brewer’s yeast). I measured the change in abdominal temperature, nocturnal activity, food intake and body mass gain in male Sprague Dawley rats injected subcutaneously with one of three doses of Brewer’s yeast (0.4, 0.2 and 4 g/kg). I further characterised the spatiotemporal activation of inflammatory mediators in the periphery (tumor necrosis factor alpha and interleukin (IL)-6) and in the brain (nuclear factor (NF) for interleukin 6, NF-kB, cyclooxygenase-2 (COX-2) and the signal transducer and activator of transcription (STAT)-3 in the vascular organ of the lamina terminalis (OVLT). Lastly, I measured the expression of hypothalamic inflammatory genes including: cytokines (IL-1b, IL-6, TNF-a), enzymes (COX-2 and microsomal prostaglandin synthase (mPGES)) and regulators of transcription factors (NF-kB inhibitor alpha (IkBa) and suppressor of cytokine signalling 3 (SOCS3)). My results show that Brewer’s yeast dose-dependently induces fever, lethargy, anorexia and body mass stunting. However, the sickness response to the high dose of Brewer’s yeast; the dose commonly used during antipyretic screening, was associated with an initial short-lived hypothermia, lengthy fevers, excessive peripheral and central inflammation and the development of an abscess. My last objective was to investigate if zymosan, a cell wall moiety of Brewer’s yeast could be used as an alternative pyrogen during antipyretic drug testing. Using the same methods as outlined for my second study, I therefore characterised the sickness responses and activation of inflammatory mediators associated with subcutaneous injection of two doses of zymosan (300 mg/kg and 30 mg/kg). My results show that zymosan dose-dependently induces fever, lethargy, anorexia and body mass stunting and that zymosan activates the same suite of inflammatory mediators as Brewer’s yeast albeit on a more moderate scale. Thus, zymosan could be used as a pyrogen for simulating fungal infections during antipyretic drug testing. In conclusion, the studies undertaken as part of my PhD have shown that among the methods and models currently recommended for use during antipyretic drug testing, rectal thermometry is associated with stress and hyperthermia which can potentially affect the accuracy and reliability of observations and conclusions drawn on the efficacy of test drugs. Additionally, at the recommended doses, Brewer’s yeast induces fever and sickness behaviours albeit with undesirable animal welfare challenges such as hypothermia, excessive inflammation and a lengthy sickness response due to the development of an abscess. However, zymosan is suitable for use as alternative to Brewer’s yeast as it is capable of inducing fever, sickness behaviours and inflammation of a moderate magnitude, which would allow pharmacological interventions without inducing animal suffering related to an excessive and prolonged inflammation.
  • No Thumbnail Available
    Item
    Effects of crude leaf extracts of Ficus thonningii on growth, gastrointestinal morphometrry and clinical biochemistry of suckling Sprague Dawley rats
    (2014-02-17) Dangarembizi, Rachael
    Ficus thonningii is a nutraceutical that is extensively used in ethnomedicine. Nursing mothers use F. thonningii leaves as nutritional and medicinal supplements and are at risk of exposing their infants to its constituent phytochemicals. The exposure of the sensitive neonatal gastrointestinal tract (GIT) to these phytochemicals can result in irreversible changes in growth and development. The objectives of this study were to determine the effects of crude F. thonningii extracts on; growth, morphology and morphometry of the abdominal viscera and clinical biochemistry of neonatal rats. Forty, suckling Sprague Dawley rats of either sex were randomly divided into 5 groups. Each group was orally gavaged once daily with either low (50 mg/kg b.w) or high (500 mg/kg b.w) doses of aqueous or methanolic extracts of F. thonningii, for 7 days. The control rats received distilled water. The pups were euthanased and tissues were collected and weighed. Samples of the liver, caecum and proximal small intestine were preserved and processed for histology. Plasma biochemical parameters were analysed colorimetrically. Data was presented as means + SD. F. thonningii extracts exhibited trophic effects on the stomach and ceacal mucosa of rats but had no significant growth-promoting effects on the small intestine and visceral organs. Histological analysis of the intestine, liver and caeca revealed no mucosal damage. Clinical chemistry parameters were not abnormally altered. There was a significant decrease (p<0.05, ANOVA) in the plasma concentrations of basal (non-fasting) glucose in the pups on the high methanolic extracts. However, the triglyceride and cholesterol levels were unaltered by the treatments. The findings suggest that F. thonningii extracts exhibit trophic effects on the mucosal layers of the stomach and caecum. F. thonningii extracts also possess glucose-lowering activity. At low doses, F. thonningii extracts can be safely used without the risk of any disruption in the structural integrity of the neonatal rat GIT and function of the liver and kidneys.