Browsing by Subject "Pharmacology"
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- ItemOpen AccessAntimalarial activity and cytotoxicity of some South African medicinal plants and their active constituents(2008) Sekhoacha, Mamello; Smith, Peter J; Campbell, William EIncludes bibliographical references (leaves 150-187).
- ItemOpen AccessAntimalarial activity and pharmacokinetic properties of new chemical entities(2013) Dambuza, Ntokozo Shirley; Smith, Peter John; Wiesner, Lubbe; Chibale, KellyIncludes abstract. Includes bibliographical references.
- ItemOpen AccessThe antimalarial potential of Ugandan traditional medicines : a study of six plants used to treat malaria symptoms(2003) Waako, Paul; Folb, Peter I; Smith, PeterThe study investigates the antimalarial potential of six Ugandan traditional medicinal plants Senecfo discifolius oliv, Senecio stuhlmannii, Indigofera emarginella steud. Ex A. Rich, Aspifia africana (Pers) C.D. Adams, Cardiospermum halicacabum L. and Momordica foetida Schumch. Et Thonn. Selection of the plants was based on ethnobotanical surveys of traditional treatment of malaria symptoms and reports from traditional healers practising in three different communities.
- ItemOpen AccessArtesunate and amodiaquine : tolerability and drug interaction study in healthy normal volunteers(2005) Orrell, Catherine; Smith, PeterIncludes bibliographical references.
- ItemOpen AccessCharacterisation of Mefloquine accumulation in Plasmodium falciparum(2003) Walden, Jason C; Smith, Peter; Folb, Peter IMefloquine has been in use for over twenty years and still very little is known about its interaction with Plasmodium falciparum. In 1979, Fitch er al carried out the only other published extensive investigation of mefloquine accumulation, but were not able to demonstrate energy dependent uptake. They later indicated that an energy requirement may be being masked by mefloquine’s ability to bind membrane phospholipids to a large extent (Chevli & Fitch, 1982).Until now no energy requirement for mefloquine accumulation has been uncovered. This thesis investigates the relationship between chloroquine and mefloquine resistance, and characterizes the mechanism of mefloquine accumulation in Plasmodium falciparum. Conditions were established that enabled the amplification of the parasites' contribution to overall mefloquine accumulation in the parasitised erythrocyte. It was found that mefloquine accumulation is stimulated by glucose and is inhibited by the glycolysis inhibitor, iodoacetate, and also by incubation at low temperature. Mefloquine accumulation was also found to be partly dependent on the pH gradient between the acidic food vacuole and the external medium. It has also been determined that mefloquine-resistant Plasmodium falciparum accumulate approximately half the amount of mefloquine than do mefloquine-sensitive parasites. It has been shown that the accumulation of both chloroquine and mefloquine have two components, a high affinity saturable component and a low affinity non-saturable component (Fitch et aI., 1979; Fitch et al., 1974; Bray et al., 1998). The saturable component has been well characterized, but until now the non-saturable component has not been identified. This thesis shows that chloroquine and mefloquine adsorption to synthetic β-haematin and pure isolated haemozoin is non-saturable. It is proposed that the malaria pigment is responsible for the low affinity, non-saturable component of chloroquine and mefloquine accumulation. The effect of chloroquine, mefloquine and artemisinin on haemoglobin levels in parasitised erythrocytes was also measured. Chloroquine caused a buildup in haemoglobin and mefloquine caused a decrease in haemoglobin levels. This adds weight to previously published work (Famin & Ginsburg, 2002) suggesting that chloroquine prevents the degradation of haemoglobin, while mefloquine inhibits the endocytosis of haemoglobin.
- ItemOpen AccessCharacterisation of the ATPase activity and study of the chloroquine accumulation properties of purified Plasmodium falciparum plasma membranes(2000) Elandalloussi, Laurence M; Smith, Peter JBibliography: p. 130-155.
- ItemOpen AccessCharacterising the role of actin and PI (3) kinases in endocytosis in the malaria parasite Plasmodium falciparum(2007) Smythe, Wynand Anton; Hoppe, Heinrich CBy contrast to mammalian cells, very little is known about endocytosis in the malaria parasite. However, endocytosis via the cytostome is required by the parasite to ingest haemoglobin from its host cytosol which it transports within double membrane vesicles to the digestive vacuole, where digestion occurs and metabolites are used mostly for nutritional purposes. To gain a deeper understanding of the molecular basis and mechanisms of this vital process, a panel of inhibitors was used to inhibit the actin cytoskeleton and PI (3) kinases in the parasite. In this study Cytochalasin D and Latrunculin A, which depolymerise and prevent actin fimalment formation, Jasplakinolide, which stabilises actin filaments, and Wormannin and LY294002, which inhibit PI 93) kinase, were used to study actin disrupting and PI (3) kinase inhibiting drug effects on haemoglobin endocytosis and transport vesicle trafficking within the malaria parasite Plasmodium falciparum.
- ItemOpen AccessThe characterization of adaptor protein homologues in Plasmodium falciparum(2009) Meredith, Sandra Allison; Hoppe, Heinrich CPlasmodium falciparum is becoming increasingly more resistant to regular antimalarial drugs, making it necessary to identify novel drug candidates and drug targets. Components of the endocytic and secretory pathway in asexual stage parasites are attractive targets because they play a fundamental role in the normal processes of parasite metabolism. Adaptor protein complexes are components of protein coats that associate with transport vesicles of the endocytic and secretory pathways in mammalian cells. Homologues of several adaptor protein subunits are encoded by the parasite genome. The presence of these genes suggests that the parasite experiences clathrin-mediated transport processes. This study reports the cloning and characterization of selected malarial homologues of these adaptor proteins, namely three medium (μ) chain adaptin homologues and two sigma (σ) chains.
- ItemOpen AccessChloroquine accumulation in Plasmodium falciparum isolated digestive vacuoles(1997) Saliba, Kevin John; Smith, Peter JDue to the development of drug-resistance by Plasmodium falciparum, the utilisation of chloroquine, a cheap and effective antimalarial has become limited. The mechanism of chloroquine-resistance is, at best, unresolved. This thesis describes an investigation of chloroquine accumulation in pure and intact Plasmodium falciparum isolated digestive vacuoles, the site of chloroquine accumulation and action. Marker enzymes and gel electrophoresis were used to demonstrate purity, and electron microscopy to verify integrity of isolated vacuoles. Using this method, vacuoles were isolated in a yield high enough to enable characterisation of chloroquine accumulation in this organelle in terms of time-, temperature-, Mg²⁺-, pH-, ATP- and other nucleotide-dependence. The chloroquine accumulating capabilities of vacuoles isolated from chloroquine-resistant and chloroquine-sensitive parasites were compared. At an external chloroquine concentration of 100 and 250nM vacuoles isolated from two chloroquine-sensitive strains accumulated significantly more chloroquine (± 3 x) than those isolated from three of the four chloroquine-resistant strains of Plasmodium falciparum tested. Although it is often suggested that the parasite digestive vacuole is involved in the mechanism of chloroquine-resistance, this is the first direct evidence to suggest this. Vacuolar proton pump inhibitors, proton gradient dissipaters, P-glycoprotein ATPase- and drug transport-inhibitors, weak bases, and structural analogues of chloroquine were used to examine the driving force of chloroquine accumulation in the isolated food vacuole. A pH gradient between the vacuole and cytoplasm is necessary to retain chloroquine in this organelle, but a chloroquine transport mechanism appears to be the main driving force in chloroquine accumulation. A polyclonal antibody directed at Pgh1, a Plasmodium falciparum homologue of P-glycoprotein, confirmed its presence on the vacuole, but was unable to inhibit chloroquine accumulation in isolated vacuoles. This thesis also shows that agents, such as verapamil, which are able to reverse chloroquine-resistance by increasing chloroquine accumulation in parasitised erythrocytes, are unable to increase chloroquine accumulation in the isolated vacuole, suggesting the involvement of an alternate site for the reversal of chloroquine-resistance.
- ItemOpen AccessA cost analysis of the treatment of first-line uncomplicated malaria in the Tonga district of Mpumalanga(1999) Wilkins, Justin; Barnes, Karen I; Folb, Peter IFollowing the completion of a detailed baseline study of malaria in the region, a model was developed to assess the cost-effectiveness of switching from chloroquine to sulfadoxine-pyrimetharnine as first line treatment in the Tonga district of Mpumalanga, South Africa, where malaria is seasonal and the population is non-immune. In vivo drug resistance was used to create a resistance variable, which was used to assess the 1997 relative costs to the health care system of employing the two drugs, analysing factors such as drug costs, staff time, transport costs, maintenance costs, utility costs, training costs and consumables costs to generate an average cost-effectiveness ratio. The model was subsequently used to estimate the average cost-effectiveness ratios of nine other potential agents for the treatment of first line malaria, including artesunate monotherapy, artesunate combinations, pyronaridine, atovaquone-proguanil, co-artemether, halofantrine, amodiaquine, and mefloquine. It was found that sulfadoxinepyrimethamine was 5 times more cost-effective as first line therapy than chloroquine. Of the other modelled drugs, it was recommended that an artesunate combination should be implemented when it becomes necessary to replace sulfadoxine-pyrimethamine; artesunate-mefloquine and artesunate-SP were estimated to be 6 times and 9 times as cost-effective as chloroquine, respectively.
- ItemOpen AccessDelivery of Vaccinia Virus Complement Control Protein (VCP) and Curcumin to the rodents' brain : implications in Alzheimer's disease and HIV dementia(2008) Kulkarni, Amod PrakashIncludes abstract. Includes bibliographical references (p. 245-262).
- ItemOpen AccessDeterminants and consequences of the pharmacokinetics of rifampicin, isoniazid, pyrazinamide and ethambutol in a cohort of tuberculosis patients(2004) McIlleron, Helen; Folb, Peter I; Little, Francesca; Smith, PeteA prospectlve pharmacokinetic study was conducted amongst a cohort of 142 patients with tuberculosis (TB) susceptible to rifampicin and isoniazid at Brewelsleloof Hospital, Worcester, in the Western Cape.
- ItemOpen AccessThe development, implementation and validation of a plasma-based high performance liquid chromatographic assay for Isoniazid and N-Acetylisoniazid: an acetylator status population study at Brewelskloof Hospital(2001) Cockcroft, Jennifer Jean; Smith, Peter; McIlleron, HelenA novel high performance liquid chromatographic assay has been developed for the simultaneous determination of isoniazid and N-acetylisoniazid in plasma. Solid phase extraction involving C18 columns is used to extract the drug and the metabolite from 0.5 ml plasma. The analyte peaks are resolved using a CB Spherisorb analytical column and ultraviolet detection at 270 nm. The assay is specific to the compounds, with consistent recovery of greater than 75% for isoniazid and over 90% for N-acetylisoniazid. The limits of detection in plasma are 300 ng/ml and 150 ng/ml for isoniazid and N-acetylisoniazid respectively. Linearity was conserved down to these concentrations. This assay was used to generate pharmacokinetic data on 114 tuberculosis patients recruited for this study at Brewelskloof hospital, Worcester, South Africa. Using these data, various markers were investigated for the determination of acetylator phenotype, namely isoniazid half-life, isoniazid plasma level at three hours, and the ratio of metabolite to drug at three hours. The ratio of metabolite to drug at three hours proved to be the most reliable method for phenotype classification, this being confirmed during the genotypic portion of the study. Trimodality was evident, although the nondiscrete separation of intermediate and rapid acetylators made this tentative. The mean values of area under the concentration-time curve for each acetylator type were found to be significantly different, with rapid acetylators being potentially compromised in terms of exposure to isoniazid (slow 32.39 mg. l⁻¹.hr, intermediate 21.25 mg. l⁻¹.hr and rapid 16.04 mg. l⁻¹.hr). Other pharmacokinetic parameters were bimodally distributed, homozygous and heterozygous rapid acetylators forming a single acetylator group. Codominance of the rapid and slow alleles was confirmed, the estimation of a mean intermediate elimination rate constant being within 7% of the observed mean. The correlation of genotype to phenotype was found to be 88.2% and the allelic distribution was determined to be acceptable using the Hardy Weinberg equation. The incidence of raised liver enzyme levels was low in the study population with no relation to acetylator phenotype. Age and weight gain after two months of daily therapy did not correlate with phenotype. The slow acetylator population comprised of a greater proportion of men, while women exhibited twice the number of rapid acetylators. No patient factors could be implicated in the apparent discordance of phenotype with genotype, and this suggests that there may be new allelic variants in this population. This report provides validation and proves the usefulness of a novel HPLC plasma-based assay for determining isoniazid and N-acetylisoniazid levels in patients with tuberculosis.
- ItemOpen AccessThe effect of quinoline anti-malarial drugs on the endolysosomal and secretory pathways of plasmodium falciparum strain 3D7, dictyostelium discoideum and mammalian A549 cells(2007) Roberts, Lindi; Hoppe, Heinrich CThe precise mechanisms of action of the quinoline anti-malarial drugs are uncertain, although they have been found to influence endocytosis, vesicular processing and secretion in malarial parasites and mammalian cells. In this study, the effects of chloroquine, amadiaquine, halofantrine, mefloquine and quinine on the endolysosomal systems in Plasmodium falciparum 3D7, Dictyostelium discoideum and A549 pulmonary cancer cells were examined.
- ItemOpen AccessExpression of the P-glycoprotein Homologue1 on food vacuoles isolated from Chloroquine-sensitive and resistant Plasmodium falciparum strains(1999) Lindt, Meinrad; Smith, Peter J; Folb, Peter IWorldwide occurrence of chloroquine resistance is an expanding problem in prophylaxis and treatment of malaria. Similarities between the drug resistance phenotype in certain cancers and in malaria suggest that homologue multidrug resistance proteins might be involved in the mechanism of resistance. In this thesis, the expression of a putative multidrug resistance protein of the malaria parasite Plasmodium falciparum, the P-glycoprotein homologue1 (Pgh1), was quantified on food vacuoles, the site of action of chloroquine. Chloroquine susceptibility was determined in 8 different P. falciparum strains. Food vacuoles were isolated from trophozoites of two chloroquine-sensitive (307 and D10) and three chloroquine-resistant (FAC8, K1 and RSA 11) strains. Antibodies against an 18 amino acid long peptide of Pgh1 were raised, as well as two other antibodies against the N-terminal ATP-binding site and the C-terminus of Pgh1. With these antibodies, Pgh1 was detected on isolated food vac.uoles and on trophozoites by immunoblotting. The exact Pgh1 expression levels on food vacuoles were measured with digital image analysis. The chloroquine-sensitive strains 307 and D10 and the chloroquine-resistant strains K1 and RSA 11 expressed equal amounts of Pgh1. The chloroquine-resistant FAC8 strain expressed at least three times more vacuolar Pgh1. No correlation was found between chloroquine IC₅₀ and vacuolar Pgh1 expression levels. Phosphorylation studies on intact food vacuoles indicated that Pgh1 is not a major kinase substrate.
- ItemOpen AccessThe interaction of verapamil with the human malaria parasite : Plasmodium falciparum(2004) Van Schalkwyk, Donelly Andrew; Smith, Peter JohnIncludes bibliographical references (leaves [129]-144).
- ItemOpen AccessThe investigation and assessment of Nutritional and Traditional Supplement products for content validity, contamination and adulteration(2013) Gabriels, Gary Anthony; Lambert, Mike; Smith, PeterNutritional supplements are used by competitive and recreational athletes of all ages. As a consequence the supplement industry has grown to meet the increasing demand. The regulation of the supplement industry is unrefined, which increases the risk of the nutritional supplements being contaminated. Contamination may be intentional, where the companies “spike” their products with an ergogenic aid, or unintentional. A consequence of contamination is that an athlete may fail a drug test after ingesting a contaminated supplement or there may be negative health consequences. Without adequate legislation it is difficult to control the industry and reduce the risk of contamination in the supplement. Objectives: To investigate the industry associated with commercially available nutritional and traditional supplements. These are in the five specific areas; (i) to review the regulations and legislations, and labelling and claims associated with nutritional products in the USA, European Union and South Africa, (ii) to assess the labelling and claims information on nutritional supplement products imported into and manufactured or assembled in South Africa, (iii) to assess using a survey questionnaire the container labelling and other sources of information that assist consumers of nutritional products in their purchasing decisions, (iv) to assess traditional commercial supplements for contamination and consistency of trace elements and heavy metals using Inductively Coupled Plasma-Mass Spectrometry, and (v) to assess the content of nutritional commercial supplements for steroids, stimulants and other compounds of interest using Tandem Liquid Chromatography-Mass Spectrometry.Methods: The thesis is divided into 6 Chapters. Chapter 1 describes the background to the problem and Chapter 2 reviews the existing legislation. In Chapter 3 the labelling and claims information on 40 nutritional supplements products are analysed, and the self-administered questionnaire determined what product label and other information influences consumers of nutritional supplements in their purchasing decisions. In Chapter 4 the consistency of trace elements and heavy metals are analysed in selected nutritional supplements using Inductively Coupled Plasma Mass Spectrometry. In Chapter 5 selected nutritional supplements are analysed for steroids, stimulants and other compounds using Tandem Liquid Chromatography Mass Spectrometry. All the data of these sections are summarised in Chapter 6.
- ItemOpen AccessAn investigation of privileged substructural motifs as templates for the discovery and design of chloroquine-resistance reversal agents(2005) Yeh, Susan; Smith, PJ; Chibale, KellyIncludes bibliographical references (leaves 152-165).
- ItemOpen AccessInvestigation of the phytochemistry and biological activity of isoquinoline alkaloids isolated from the South African medicinal plants, cyrtanthus sanguineus (Lindl.) walp. and cyrtanthus obliquus (L.f.)ait(2001) Brine, Natalie Dawn; Campbell, William E; Smith, Peter J; Folb, Peter IThe term "traditional medicine" refers to the ways of protecting and restoring health that existed before the arrival of modern medicine. These approaches to health belong to the traditions of each country and have been handed down from generatio to generation.
- ItemOpen AccessIsolation and characterisation of antiplasmodial compounds from Xerophyta species and the bioavailability, metabolic and efficacy evaluation of 9-0-acetylhydnocarpin in a mouse model(2008) Wiesner, Lubbe; Smith, Peter J; Campbell, William EIncludes abstract. Includes bibliographical references (leaves 237-265).