Browsing by Author "Smith, Peter J"

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    Antimalarial activity and cytotoxicity of some South African medicinal plants and their active constituents
    (2008) Sekhoacha, Mamello; Smith, Peter J; Campbell, William E
    Includes bibliographical references (leaves 150-187).
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    The antimalarial activity of Dicoma anomala and the chloroquine resistance reversing effects of Sclerocarya birrea on Plasmodium falciparum in vitro
    (2001) Matsabisa, Motlalepula Gilbert; Folb, Peter I; Smith, Peter J; Campbell, William E
    Two plants, Dicoma anomala [Sond.]; a member of the Asteraceae and Sclerocarya birrea [(A. Rich) Hoechst. subspecies caffra (Sond.) Kokwaro], a member of the Anarcadiaceae families, are used widely in Africa for a variety of traditional treatments. In this thesis it has been shown that these plants possess in vitro pharmacological activities against the malaria parasite. The extracts of D. anomala are active in vitro against Plasmodium falciparum and those of S. birrea selectively enhance the in vitro accumulation of chloroquine in resistant strains of Plasmodium falciparum.
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    Antimycobacterial activity of the red algae gelidium pristoides, plocamium corallorhiza and polysiphonia virgata
    (2006) Saravanakumar, Denise; Folb, Peter I; Smith, Peter J; Campbell, William E
    In 1993, the World Health Organisation declared tuberculosis a global health emergency. Currently, efforts are underway to improve the way the disease is managed and to find more effective treatments that would combat the problem of long treatment periods, toxicity, drug-resistance and HIV-coinfection. In the process, natural product chemistry continues to play an important role in the search for new compounds to treat tuberculosis. Terrestrial plants have been investigated for antimycobacterial activity, while marine plants are yet to receive as much attention. In this project, three South African marine plants were drawn into the search for novel anti-tuberculosis compounds. One of the seaweeds is already part of the local seaweed industry, namely Gelidium pristoides, while Plocamium corallorhiza and Polysiphonia virgata have economic potential. These three red algae were extracted extensively and fractionated using preparative layer chromatography and preparative centrifugally accelerated radial thin-layer chromatography (Chromatotron). The crude extracts of the algae showed no inhibitory activity to growth of the causative agent of human tuberculosis, Mycobacterium tuberculosis. However, when the purified fractions were tested against M. tuberculosis in the BACTEC-460 radiometric method at a concentration of 125 μg/mL, fractions 322, 323 and 333 of P. virgata showed 100% inhibition, while two fractions of G. pristoides showed 91.7% and 79.2% inhibition, respectively. Two fractions of P. corallorhiza demonstrated 41.2% and 73.5% inhibition. The bioactive fractions of P. virgata were further purified and resulted in the isolation of a known compound namely, 2-methoxyethyl-2-methacrylate (MEMA). When MEMA was tested by radiometric assay against M. tuberculosis, it showed anti-tuberculosis activity at a MIC-value of 100 μg/mL and no cytotoxicity against Chinese hamster ovarian cells. However, in a re-investigation into the bioactive compounds of P. virgata it was established that MEMA was not the major bioactive compound. Long chain fatty acids were responsible for the antimycobacterial activity of the algal extract particularly oleic acid, linoleic acid, dodecanoic acid, and myristic acid. Oleic acid inhibited the growth of M. tuberculosis at and MIC-value of 25 11 g/rnL, while dodecanoic acid, myristic acid and linoleic acid all had MIC-values of 50 μg/mL. Stearic acid and palmitic acid was also isolated from the seaweed, but only moderate inhibition of M. tuberculosis was observed for at MIC-values of 50 μg/mL. Oleic acid showed moderate inhibition at 50 μg/mL against the multi-drug resistant isolate of M. tuberculosis, while myristic acid and dodecanoic acid showed significant inhibition against the same at 50 μg/mL and moderate inhibition at 25 μg/mL. Linoleic acid also inhibited the growth of the multi-drug resistant strain at 50 μg/mL. Oleic acid showed the most inhibition of the growth of M. smegmatis in direct bioautography with an MIC-value of 0.8 μg/mL, while linoleic acid and dodecanoic acid had MIC-values of 1.56 μg/mL and 3.125 μg/mL., respectively. Stearic acid, palmitic acid, and myristic acid did not inhibit the growth of M. smegmatis.
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    The antiplasmodial, toxicity and pharmacokinetic properties of synthetic derivatives of the natural product Curcumin
    (2008) Okalebo, Faith Apolot; Smith, Peter J; Chibale, Kelly; Guantai, Anastasia N
    Includes bibliographical references.
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    Association of lopinavir concentrations with plasma lipid or glucose concentrations in HIV-infected South Africans: a cross sectional study
    (BioMed Central Ltd, 2012-10-26) Sinxadi, Phumla Z; McIlleron, Helen M; Dave, Joel A; Smith, Peter J; Levitt, Naomi S; Maartens, Gary
    Abstract Background Dyslipidaemia and dysglycaemia have been associated with exposure to ritonavir-boosted protease inhibitors. Lopinavir/ritonavir, the most commonly used protease inhibitor in resource-limited settings, often causes dyslipidaemia. There are contradictory data regarding the association between lopinavir concentrations and changes in lipids. Aim To investigate associations between plasma lopinavir concentrations and lipid and glucose concentrations in HIV-infected South African adults. Methods Participants stable on lopinavir-based antiretroviral therapy were enrolled into a cross-sectional study. After an overnight fast, total cholesterol, triglycerides, and lopinavir concentrations were measured and an oral glucose tolerance test was performed. Regression analyses were used to determine associations between plasma lopinavir concentrations and fasting and 2 hour plasma glucose, fasting cholesterol, and triglycerides concentrations. Results There were 84 participants (72 women) with a median age of 36 years. The median blood pressure, body mass index and waist: hip ratio were 108/72 mmHg, 26 kg/m2 and 0.89 respectively. The median CD4 count was 478 cells/mm3. Median duration on lopinavir was 18.5 months. The median (interquartile range) lopinavir concentration was 8.0 (5.2 to 12.8) μg/mL. Regression analyses showed no significant association between lopinavir pre-dose concentrations and fasting cholesterol (β-coefficient −0.04 (95% CI −0.07 to 0.00)), triglycerides (β-coefficient −0.01 (95% CI −0.04 to 0.02)), fasting glucose (β-coefficient −0.01 (95% CI −0.04 to 0.02)), or 2-hour glucose concentrations (β-coefficient −0.02 (95% CI −0.09 to 0.06)). Lopinavir concentrations above the median were not associated with presence of dyslipidaemia or dysglycaemia. Conclusions There was no association between lopinavir plasma concentrations and plasma lipid and glucose concentrations.
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    Chemical modification and pharmacological evaluation of the antimalarial natural product totarol
    (2004) Tacon, Claire; Smith, Peter J; Chibale, Kelly; Campbell, William E
    Includes bibliographical references.
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    Chloroquine accumulation in Plasmodium falciparum isolated digestive vacuoles
    (1997) Saliba, Kevin John; Smith, Peter J
    Due 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.
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    Expression 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 I
    Worldwide 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.
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    In vitro efficacy tests against Mycobacterium species of South African traditional medicinal plants
    (2002) Ntutela, Siyabulela Calvin Sibusiso; Folb, Peter I; Smith, Peter J; Steyn, Lafras
    Tuberculosis is the leading cause of death due to a single organism; with a mortality of more than 3million people each year, worldwide. The emergence of multi-drug resistance and HIV/AIDS are the major causes of this problem. New therapeutic agents with a different mode of action, and thereby of resistance to Mycobacterium tuberculosis, the causative agent, are needed urgently. Amongst the methods used, the area of ethnopharmacology is explored in this study. Visits were performed to collect the plants used by traditional healers in 7 provinces of South Africa for the treatment of tuberculosis.
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    In vivo effects of South African traditional medicines against Mycobacterium tuberculosis in experimental mice
    (2001) Bapela, Nchinya Benedict; Ryffel, Bernhard; Smith, Peter J
    Although it is more than 100 years since Robert Koch discovered the tubercle bacillus, and more than 40 years since effective chemotherapy became available, the incidence of tuberculosis is increasing in much of the developing world and has recently re-emerged as a public health problem in industrialized countries. This problem is compounded by the increase in host susceptibility to tuberculosis caused by co-infection with HIV (Human Immunodeficiency Virus) and the emergence of Mycobacterium tuberculosis strains that are resistant to the front-line drugs. These factors highlight the urgent need for development of new drug classes to counter the threat posed by tuberculosis. The purpose of the present study was to develop a mouse model for Mycobacterium tuberculosis with the aim of determining the antimycobacterial activity of medicinal plants used by traditional doctors to treat tuberculosis in South Africa. Furthermore, the toxic effects of these medicinal plants in uninfected mice were determined. A field trip to the Northern Cape, Western Cape, Eastern Cape and Free State provinces was undertaken and medicinal plants used by traditional doctors to treat tuberculosis or its symptoms were collected, identified and examined for their therapeutic effects against Mycobacterium tuberculosis, determined using the mouse model. In addition, the effects of medicinal plants on the production of cytokines and granuloma formation in infected mice were examined. Six-to-ten week old C57BL/6 mice were infected with 107 viable Mycobacterium tuberculosis H37Rv strain by an aerosol exposure model. Bacterial growth was monitored by sacrificing infected but untreated mice at day 1, week 2 and week 4. Treatment with medicinal plant extracts was started 2 weeks after infection and continued for 2 weeks. An INH-RIF combination was used as positive controls. The bacterial load in infected but untreated mice increased by 1 log unit each week for 2 to 3 weeks. Bacterial loads were not detected in INH-RIF treated mice after 2 weeks of treatment. Treatment of mice with high doses of plant extracts was toxic. None of the tested medicinal plant extracts showed any activity against Mycobacterium tuberculosis. The production of IL-12 at week 4 was suppressed/ decreased when plant extract A was given at different concentrations. The bacterial loads in the lungs of the plant extract A treated mice was higher than that of the untreated mice (p < 0.005). Histological analysis of the lungs also revealed a high number of bacilli and increased size of the formed granuloma. In conclusion, the selected plant extracts obtained by water extraction exhibited no anti-tuberculosis activity in the laboratory mouse model for Mycobacterium tuberculosis infection. Furthermore, it was also shown that some plant extracts suppressed the production of IL-12, which plays an important role in the host's defense against Mycobacterium tuberculosis. However, further work is required to test if treatment for longer periods exhibits antituberculous activity.
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    Investigation 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 I
    The 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.
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    Isolation 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 E
    Includes abstract. Includes bibliographical references (leaves 237-265).
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    Isolation and characterization of antiplasmodial compounds from Siphonochilus aethiopicus and Aloe ferox and bioavailability of a novel furanoterpenoid
    (2008) Lategan, Carmen; Smith, Peter J; Campbell, William E
    Includes abstract. Includes bibliographical references (leaves 138-162).
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    The isolation of anti-mycobacterial compounds from South African medicinal plants
    (2005) Madikane, Eliya Vukani; Smith, Peter J; Campbell, William E; Elisha, G B
    Includes bibliographical references.
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    A post-mortem toxicological investigation: Understanding the role of drugs of abuse in violent fatalities in Cape Town, South Africa
    (2016) Auckloo, Marie Belle Kathrina Mendoza; Davies, Bronwen; Smith, Peter J
    Violence and resulting injuries are critical health burdens worldwide, accounting for the death of millions of individuals annually. The literature reports an association between drug use and violence, providing data indicating that the use of psychoactive substances increases the risk of morbidity and mortality due to violent acts. South Africa has a long history of violence, with one of the highest rates of recorded violence- and injury-related deaths in the world. This is complicated by an increase in illicit substance use and abuse, particularly in the Cape Town Metropole, located within the Western Cape Province. The use of toxicological findings from victims of violent death (homicides, suicides, and accidents) to examine community-specific drug-related violence is slowly increasing in different parts of the world. In South Africa, however, monitoring drug trends in violent fatalities using toxicological analysis is uncommon, and hence drug toxicology of violent-related fatalities is limited. Divided into three contextual sections, this research study focuses on the post-mortem toxicology of violent deaths in a South African setting. The first section provides a general idea of the research problem and an initial development of the investigation process. The second section provides a theoretical basis for performing routine toxicological analyses in deaths due to violence, reports important research work conducted in the field worldwide, and emphasizes the need to monitor toxicological data derived from violent fatalities in Cape Town, South Africa. The last section, in the form of a manuscript, presents the overall research study including the methodology, outcomes, and concluding findings in a concise and illustrative manner. The primary aim of this pilot study was to investigate the prevalence and characteristics of illicit substances in violent fatalities (homicides, suicides, and accidents) of the Salt River mortuary in Cape Town, South Africa. The objectives were to conduct a comprehensive drug toxicology analysis to generate qualitative and comparative data from the aforementioned cases. In addition, this study investigated the dynamics between psychoactive substance use and violent deaths in terms of toxicological trends, and the demographics and circumstances of death of the victim. Lastly, the author discusses potential qualitative associations between illicit substances and violence-related deaths in a South African setting, and provide suggestions for future toxicological analyses in these fatalities.
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    The role of the pharmacokinetics, host folate levels and parasite mutations in the in vivo efficacy of pyrimethamine-sulfadoxine against Plasmodium falciparum
    (2003) Dzinjalamala, Fraction Kunseu; Smith, Peter J; Kublin, James G
    Includes bibliographical references.
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    Studies on in vitro antiplasmodial activity of cleome rutidosperma
    (2010) Bose, Anindya; Lategan, Carmen Abriette; Smith, Peter J; Gupta, Jayanta Kumar
    Malaria is a protozoal disease transmitted by the Anopheles mosquito, caused by minute parasitic protozoa of the genus Plasmodium, which infect human and insect hosts alternatively. It affects over 40% of the worldís population, with 120 million cases reported, and about 2 million deaths annually (1). The P. falciparum variety of the parasite accounts for 80% of cases and 90% of deaths caused by malaria. The declining efficacy of classical medication in relation to the rapid increase of parasite resistant strains, mainly of Plasmodium falciparum, as well as the greater resistance of vectors to insecticides, and the difficulty of creating efficient vaccines have led to an urgent need for new efficient antimalarial drugs (2, 3). Natural molecules may provide innovative strategies towards malarial control, hence active research groups are now working to develop new active compounds as an alternative to chloroquine, especially from artemisinin (4, 5), a plant-based antimalaria drug isolated from the Chinese plant Artemisia annua (6). Plants may well, therefore, prove to be the sources of new antimalarial in view of the success with the two important chemotherapeutic agents, quinine and artemisinin, both of which are derived from plants. Cleome rutidosperma (Capparidaceae) is a low-growing herb, up to 70 cm tall, found in waste grounds and grassy places with trifoliate leaves and small, violet-blue flowers, which turn pink as they age. The elongated capsules display the asymmetrical, dull black seeds. The plant is native to West Africa, although it has become naturalized in various parts of tropical America as well as Southeast Asia (7, 8). The diuretic, laxative, anthelmintic, antimicrobial, analgesic, anti-inflammatory, antipyretic, antioxidant and free radical scavenging activities of Cleome rutidosperma were reported earlier by the authors (9-13). The plant is used as antimalarial by the traditional healers in Cameroon and mild antiplasmodial activity of chloroform/methanol (1:1) extract of leaves of Cleome rutidosperma against chloroquine-sensitive (F32) laboratory strain of P. falciparum was reported earlier in Cameroon (14). The present study investigates the in vitro antiplasmodial activity of ethanolic extract and its fractions of aerial parts of Cleome rutidosperma against the chloroquine sensitive (CQS) D10 strain of the parasite, as well as their toxicity against a mammalian cell lines.