Browsing by Author "Smith, Peter"
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- ItemOpen AccessA Review of Psychotropic drug prescription for patients with Intellectual disability at Alexandra Hospital (a specialist Intellectual Disability psychiatric hospital) outpatient clinic(2021) Akpabio, Idorenyin Ubon; Kleintjes, Sharon; Smith, PeterBackground: People with intellectual disability are more likely than the general population to be prescribed psychotropic agents. The most common indications include treatment of a psychiatric disorder and management of behaviours that challenge. Aim: The study aimed to assess the prescribing patterns of psychotropic medication to outpatients with intellectual disability at a psychiatric hospital. Setting: Alexandra hospital outpatient clinic, Cape Town. Methods: This was a retrospective folder and prescription chart review. Folders of all new patients (103) seen between January 2018 and August 2019 were examined at two points, the initial appointment and again at six months. The information was examined against the World Psychiatric Association (WPA) and the National Institute for Health and Care Excellence (NICE) guidelines for prescribing in people with intellectual disability. Results: psychotropic medication was prescribed to 88% of patients. Antipsychotics accounted for more than 56% of the medication prescribed and was used mainly to manage behaviours that challenge. Clinicians at Alexandra hospital followed prescribing guidelines to some extent; however, more still needs to be done to ensure best practice and care. Conclusion: This review revealed a few shortcomings in meeting prescribing guidelines by clinicians at Alexandra hospital. Measures to address these shortcomings could be the inclusion of medication review schedules and standardised forms for clerking and monitoring of side effects in patient files, the use of behavioural strategies as the primary management of behaviours that challenge, and the performance of regular clinical practice audits.
- 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 AccessAssociation of lopinavir concentrations with plasma lipid or glucose concentrations in HIV-infected South Africans: a cross sectional study(BioMed Central Ltd, 2012) Sinxadi, Phumla; McIlleron, Helen; Dave, Joel; Smith, Peter; Levitt, Naomi; Maartens, GaryBACKGROUND: 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) mug/mL. Regression analyses showed no significant association between lopinavir pre-dose concentrations and fasting cholesterol (beta-coefficient 0.04 (95% CI 0.07 to 0.00)), triglycerides (beta-coefficient 0.01 (95% CI 0.04 to 0.02)), fasting glucose (beta-coefficient 0.01 (95% CI 0.04 to 0.02)), or 2-hour glucose concentrations (beta-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.
- 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 AccessComplementary and alternate medicines: a forensic analysis of the potential adulteration of over-the-counter anorectics and "lifestyle" medicines in South Africa(2017) Catterson, Sandra Lynne; Davies, Bronwen; Smith, Peter; Aukloo, Kathrina MendozaBackground: Complementary and Alternate Medicines (CAMs) in South Africa are not yet subjected to the same rigorous testing required for allopathic (prescription) medication, yet they are freely available as over-the-counter medicines. Past research has shown the presence of a banned drug, sibutramine in natural anorectics and a schedule 6 prescription drug, sildenafil, found in natural erectile dysfunction preparations. Methods: Initially, 26 exhibits (18 erectile dysfunction medicines and 8 anorectics) were screened for active pharmaceutical ingredients using high performance liquid chromatography tandem mass spectrometry. An AB SCIEX 3200 TRAP® linear ion-trap quadrupole mass spectrometer was used to detect and subsequently quantitate these active pharmaceutical ingredients using a targeted multiple reaction monitoring mode. Samples were extracted with 50% v/v methanol in water. A method for the quantitation of sildenafil was subsequently partially validated. The intra- and inter-assay precisions were evaluated and the linearity of the method was investigated in the range of 20 ng/mL to 2000 ng/mL. The method was then successfully applied to a random selection of CAMs. A random sample (n=61) of erectile dysfunction CAMs were selected for quantitation from two different clusters. Cluster 1 comprised of supermarkets and cluster 2 of pharmacies. Results: The validation method for sildenafil showed that the limit of detection was 1.09 ng/mL and the limit of quantitation was 20 ng/mL. The correlation co-efficient and bias were less than 20%. Initial screening of the 26 exhibits indicated that sildenafil was present in 12 of the 18 samples tested and sibutramine in 6 of the 8 anorectics. Of the later 61 exhibits tested, 43 tested positive for sildenafil. The mass of sildenafil per sample ranged from 1.09 ng/mL to 123.7 mg/sample. Conclusion: The lack of label content, regulation and legislation exposes the consumer to the risk of consuming an active pharmaceutical ingredient which may very likely have an adverse effect on their health. There is a need to raise public awareness to the potential dangers of unregulated CAMs, encourage doctors to become more aware of their patients' consumption of CAMs and to motivate the Medicines Control Council to follow through with their deadlines for the regulation of CAMs.
- ItemOpen AccessThe correlation between raised liver enzyme levels and high concentrations of rifampicin and its metabolites : 25-desacetyl rifampicin and 3-formyl rifampicin(2001) Reuter, Galya Dominique; Smith, PeterBibliography: leaves [98]-109.
- ItemOpen AccessCurcumin-related hybrid compounds as potential antimalarial agents : design, synthesis, mechanistic investigations, biological evaluation and pharmacokinetic studies(2010) Guantai, Eric; Chibale, Kelly; Smith, PeterMalaria remains one of the most devastating tropical diseases, with staggering infection and mortality statistics. Over 200 million clinical cases of malaria (resulting in 1 - 3 million deaths) are reported annually. Africa bears the greatest burden of this disease. with the vast majority of malaria cases (>85%). and malaria-related deaths (>90%). being reported in sub-Saharan Africa. The main challenge to malaria control has been the development of clinically significant resistance Of the parasite to most known antimalarial drugs. This suggests that the development of new, highly efficadous drugs and/or treatment regimens for the management of malaria remains a key priority. This study applied molecular hybridization as a strategy in the development of novel potential antimalarial agents. The aim was to try and identify novel hybrid compounds containing scaffolds that are structurally related to the natural product curcumin, and which exhibit in vitro and in vivo antimalarial activity. Part of the study involved investigations into the pharmacokinetics and possible antimalarial mechanisms of action of selected target compounds.
- ItemOpen AccessDetermination of biomarkers for toxicity and antiretroviral adherence in hair in South African patients(2018) Johnston, Jenna; Wiesner, Lubbe; Smith, PeterBackground: Substance abuse is one of the many factors associated with poor levels of antiretroviral adherence and is also prevalent among HIV-infected individuals. Ethyl glucuronide, a minor metabolite of alcohol, is a stable biomarker in hair that can be used to detect and monitor alcohol consumption over long time periods. Drugs of abuse are also detected in hair. Hair provides a longer window of drug detection compared to blood and urine. Recently, hair has also been studied as an alternative matrix for adherence monitoring and concentrations of antiretrovirals in hair have been shown to be closely correlated with virologic outcomes. This study investigated the impact of substance abuse on adherence among HIV-infected patients attending an antiretroviral therapy clinic in Cape Town by measuring drug concentrations in hair. Efavirenz levels in hair were also measured to investigate the usefulness of using hair analysis as a method of adherence monitoring within the South African context. Method: This study describes the development and validation of three liquid chromatography tandem mass spectrometry methods of hair analysis. The first method developed was for the quantification of ethyl glucuronide in 20 mg samples of hair. This method was validated over the calibration range 7.5 - 480 pg/mg. Secondly, a qualitative method was developed to screen hair samples for amphetamine, methamphetamine, cocaine, benzoylecgonine, cocaethylene and methaqualone. The final method developed was for the quantification of efavirenz in 0.2 mg samples of hair. This method was validated over the calibration range 0.625 - 40 ng/mg. The validated methods were applied to 257 samples of hair collected from 135 HIV-infected patients during visits to the clinic at weeks 16, 32 and 48. The results generated from the analysis of the hair samples were analysed in the context of additional adherence measurements collected for a related randomized controlled study. Results: Analysis of the hair samples for ethyl glucuronide demonstrated that 27% of the samples analysed contained levels above 30 pg/mg which is the cutoff value suggested by the Society of Hair Testing to identify heavy drinkers. The results also show limitations to using the CAGE alcohol abuse screening tool which had a poor sensitivity of only 28.8%. Eight (5.9%) out of the 135 participants were identified to be chronic drug users, and of these five (62.5%) were identified to be heavy drinkers as well. The most commonly abused drug identified in the screen was methaqualone. The median efavirenz levels at weeks 16, 32 and 48 were 5.52 ng/mg (IQR: 3.60 - 9.77), 5.75 ng/mg (IQR: 3.21 - 8.18) and 4.89 ng/mg (IQR: 3.10 - 7.94) respectively. Participants with the poor CYP2B6 metaboliser genotype had significantly higher median efavirenz hair concentrations compared to participants with intermediate and extensive genotypes (P < 0.0001). Efavirenz levels in hair and plasma samples were strongly correlated throughout the study (Spearman correlation coefficients: 0.672 - 0.741, all P values < 0.0001). Substance abuse had no impact on adherence measured by an electronic adherence monitoring device. No significant correlation was observed between adherence and levels of efavirenz in hair. Conclusions: Methods of hair analysis were developed and successfully applied to hair samples in the context of better understanding the impact of substance abuse on adherence. The results from the analysis of the hair samples provided insight into the prevalence of substance abuse among HIV-infected patients. The strong correlation observed between levels of efavirenz in hair and plasma suggest that, in this subset of HIV-infected patients, a single plasma concentration was as good an adherence measure as a hair concentration. The hair analysis methods developed and validated in this study are novel in South Africa and demonstrate the potential of this matrix to be used in various contexts within the country.
- ItemOpen AccessDetermination of the effect of blood testing intervals on bioavailability and bioequivalence assessment of fixed-dose drug combination anti-tuberculosis drugs(2003) Gabriels, Gary Anthony; Folb, Peter I; Smith, Peter
- ItemOpen AccessDevelopment and partial validation of a method for the quantification of benzodiazepines and antidepressants in whole blood, serum and urine by liquid chromotography - Tandem mass spectrometry(2015) Pieters, Janke; Smith, PeterThe aim of this project is to develop a single quantification method for certain benzodiazepines, opiates and antidepressants in whole blood, serum and urine by LC-MS/M5 and to consequently validate the analytical method for official use in the Division of Pharmacology at the University of Cape Town.
- ItemOpen AccessDevelopment of a method for the screening and quantification of methamphetamine, and its major metabolite amphetamine, in hair using liquid chromatography-tandem mass spectrometry(2015) Johnston, Jenna; Smith, Peter; Heyns, MariseHair has, over recent years, become widely recognised as an alternate or complementary matrix to blood and urine for drug analysis. Hair analysis offers a wider detection window after drug exposure than blood or urine testing and can provide a long-term history of an individual’s drug use. There are several practical applications of hair analysis for drugs including workplace drug testing, doping control, driving licence re-granting, drug-related deaths and drug-facilitated crimes. As a result hair analysis is currently being performed within various toxicological fields in laboratories around the world. However, before the start of this study no hair analysis for drugs was being performed in South Africa. Therefore, the main aim of this study, as stated in Chapter 1, was to develop a method for the detection and quantification of drugs of abuse, specifically methamphetamine and amphetamine, in hair using High Performance Liquid Chromatography coupled to Mass Spectrometry.
- 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 AccessDisruption of maternal gut microbiota during gestation alters offspring microbiota and immunity(BioMed Central, 2018-07-07) Nyangahu, Donald D; Lennard, Katie S; Brown, Bryan P; Darby, Matthew G; Wendoh, Jerome M; Havyarimana, Enock; Smith, Peter; Butcher, James; Stintzi, Alain; Mulder, Nicola; Horsnell, William; Jaspan, Heather BBackground: Early life microbiota is an important determinant of immune and metabolic development and may have lasting consequences. The maternal gut microbiota during pregnancy or breastfeeding is important for defining infant gut microbiota. We hypothesized that maternal gut microbiota during pregnancy and breastfeeding is a critical determinant of infant immunity. To test this, pregnant BALB/c dams were fed vancomycin for 5 days prior to delivery (gestation; Mg), 14 days postpartum during nursing (Mn), or during gestation and nursing (Mgn), or no vancomycin (Mc). We analyzed adaptive immunity and gut microbiota in dams and pups at various times after delivery. Results In addition to direct alterations to maternal gut microbial composition, pup gut microbiota displayed lower α-diversity and distinct community clusters according to timing of maternal vancomycin. Vancomycin was undetectable in maternal and offspring sera, therefore the observed changes in the microbiota of stomach contents (as a proxy for breastmilk) and pup gut signify an indirect mechanism through which maternal intestinal microbiota influences extra-intestinal and neonatal commensal colonization. These effects on microbiota influenced both maternal and offspring immunity. Maternal immunity was altered, as demonstrated by significantly higher levels of both total IgG and IgM in Mgn and Mn breastmilk when compared to Mc. In pups, lymphocyte numbers in the spleens of Pg and Pn were significantly increased compared to Pc. This increase in cellularity was in part attributable to elevated numbers of both CD4+ T cells and B cells, most notable Follicular B cells. Conclusion Our results indicate that perturbations to maternal gut microbiota dictate neonatal adaptive immunity.
- ItemOpen AccessEffects of amodiaquine and artesunate on sulphadoxine-pyrimethamine pharmacokinetic parameters in children under five in Mali(BioMed Central Ltd, 2011) Tekete, Mamadou; Toure, Sekou; Fredericks, Alfia; Beavogui, Abdoul; Sangare, Cheick; Evans, Alicia; Smith, Peter; Maiga, Hamma; Traore, Zoumana; Doumbo, Ogobara; Barnes, Karen; Djimde, AbdoulayeBACKGROUND:Sulphadoxine-pyrimethamine, in combination with artesunate or amodiaquine, is recommended for the treatment of uncomplicated malaria and is being evaluated for intermittent preventive treatment. Yet, limited data is available on pharmacokinetic interactions between these drugs. METHODS: In a randomized controlled trial, children aged 6-59 months with uncomplicated falciparum malaria, received either one dose of sulphadoxine-pyrimethamine alone (SP), one dose of SP plus three daily doses of amodiaquine (SP+AQ) or one dose of SP plus 3 daily doses of artesunate (SP+AS). Exactly 100 mul of capillary blood was collected onto filter paper before drug administration at day 0 and at days 1, 3, 7, 14, 21 and 28 after drug administration for analysis of sulphadoxine and pyrimethamine pharmacokinetic parameters. RESULTS: Fourty, 38 and 31 patients in the SP, SP+AQ and SP+AS arms, respectively were included in this study. The concentrations on day 7 (that are associated with therapeutic efficacy) were similar between the SP, SP+AQ and SP+AS treatment arms for sulphadoxine (median [IQR] 35.25 [27.38-41.70], 34.95 [28.60-40.85] and 33.40 [24.63-44.05] mug/mL) and for pyrimethamine (56.75 [46.40-92.95], 58.75 [43.60-98.60] and 59.60 [42.45-86.63] ng/mL). There were statistically significant differences between the pyrimethamine volumes of distribution (4.65 [3.93-6.40], 4.00 [3.03-5.43] and 5.60 [4.40-7.20] L/kg; p = 0.001) and thus elimination half-life (3.26 [2.74 -3.82], 2.78 [2.24-3.65] and 4.02 [3.05-4.85] days; p < 0.001). This study confirmed the lower SP concentrations previously reported for young children when compared with adult malaria patients. CONCLUSION: Despite slight differences in pyrimethamine volumes of distribution and elimination half-life, these data show similar exposure to SP over the critical initial seven days of treatment and support the current use of SP in combination with either AQ or AS for uncomplicated falciparum malaria treatment in young Malian children.
- ItemOpen AccessFast in vitro methods to determine the speed of action and the stage-specificity of anti-malarials in Plasmodium falciparum(BioMed Central Ltd, 2013) Le Manach, Claire; Scheurer, Christian; Sax, Sibylle; Schleiferbock, Sarah; Cabrera, Diego; Younis, Yassir; Paquet, Tanya; Street, Leslie; Smith, Peter; Ding, Xavier; Waterson, David; Witty, Michael; Leroy, Didier; Chibale, Kelly; Wittlin, SergioBACKGROUND: Recent whole cell in vitro screening campaigns identified thousands of compounds that are active against asexual blood stages of Plasmodium falciparum at submicromolar concentrations. These hits have been made available to the public, providing many novel chemical starting points for anti-malarial drug discovery programmes. Knowing which of these hits are fast-acting compounds is of great interest. Firstly, a fast action will ensure rapid relief of symptoms for the patient. Secondly, by rapidly reducing the parasitaemia, this could minimize the occurrence of mutations leading to new drug resistance mechanisms.An in vitro assay that provides information about the speed of action of test compounds has been developed by researchers at GlaxoSmithKline (GSK) in Spain. This assay also provides an in vitro measure for the ratio between parasitaemia at the onset of drug treatment and after one intra-erythrocytic cycle (parasite reduction ratio, PRR). Both parameters are needed to determine in vitro killing rates of anti-malarial compounds. A drawback of the killing rate assay is that it takes a month to obtain first results. METHODS: The approach described in the present study is focused only on the speed of action of anti-malarials. This has the advantage that initial results can be achieved within 4-7 working days, which helps to distinguish between fast and slow-acting compounds relatively quickly. It is expected that this new assay can be used as a filter in the early drug discovery phase, which will reduce the number of compounds progressing to secondary, more time-consuming assays like the killing rate assay. RESULTS: The speed of action of a selection of seven anti-malarial compounds was measured with two independent experimental procedures using modifications of the standard [3H]hypoxanthine incorporation assay. Depending on the outcome of both assays, the tested compounds were classified as either fast or non-fast-acting. CONCLUSION: The results obtained for the anti-malarials chloroquine, artesunate, atovaquone, and pyrimethamine are consistent with previous observations, suggesting the methodology is a valid way to rapidly identify fast-acting anti-malarial compounds. Another advantage of the approach is its ability to discriminate between static or cidal compound effects.
- ItemOpen AccessIn vitro anti-plasmodial activity of Dicoma anomala subsp. gerrardii (Asteraceae): identification of its main active constituent, structure-activity relationship studies and gene expression profiling(BioMed Central Ltd, 2011) Becker, John; van der Merwe, Marina; van Brummelen, Anna; Pillay, Pamisha; Crampton, Bridget; Mmutlane, Edwin; Parkinson, Chris; van Heerden, Fanie; Crouch, Neil; Smith, Peter; Mancama, Dalu; Maharaj, VineshBACKGROUND: Anti-malarial drug resistance threatens to undermine efforts to eliminate this deadly disease. The resulting omnipresent requirement for drugs with novel modes of action prompted a national consortium initiative to discover new anti-plasmodial agents from South African medicinal plants. One of the plants selected for investigation was Dicoma anomala subsp. gerrardii, based on its ethnomedicinal profile. METHODS: Standard phytochemical analysis techniques, including solvent-solvent extraction, thin-layer- and column chromatography, were used to isolate the main active constituent of Dicoma anomala subsp. gerrardii. The crystallized pure compound was identified using nuclear magnetic resonance spectroscopy, mass spectrometry and X-ray crystallography. The compound was tested in vitro on Plasmodium falciparum cultures using the parasite lactate dehydrogenase (pLDH) assay and was found to have anti-malarial activity. To determine the functional groups responsible for the activity, a small collection of synthetic analogues was generated - the aim being to vary features proposed as likely to be related to the anti-malarial activity and to quantify the effect of the modifications in vitro using the pLDH assay. The effects of the pure compound on the P. falciparum transcriptome were subsequently investigated by treating ring-stage parasites (alongside untreated controls), followed by oligonucleotide microarray- and data analysis. RESULTS: The main active constituent was identified as dehydrobrachylaenolide, a eudesmanolide-type sesquiterpene lactone. The compound demonstrated an in vitro IC50 of 1.865 muM against a chloroquine-sensitive strain (D10) of P. falciparum. Synthetic analogues of the compound confirmed an absolute requirement that the alpha-methylene lactone be present in the eudesmanolide before significant anti-malarial activity was observed. This feature is absent in the artemisinins and suggests a different mode of action. Microarray data analysis identified 572 unique genes that were differentially expressed as a result of the treatment and gene ontology analysis identified various biological processes and molecular functions that were significantly affected. Comparison of the dehydrobrachylaenolide treatment transcriptional dataset with a published artesunate (also a sesquiterpene lactone) dataset revealed little overlap. These results strengthen the notion that the isolated compound and the artemisinins have differentiated modes of action. CONCLUSIONS: The novel mode of action of dehydrobrachylaenolide, detected during these studies, will play an ongoing role in advancing anti-plasmodial drug discovery efforts.
- ItemOpen AccessIntegration of In Silico and In Vitro ADMET properties in lead identification and optimization of compounds for the treatment of parasitic diseases(2012) Thelingwani, Roslyn; Chibale, Kelly; Masimirembwa, Collen; Smith, PeterParasitic infections are the major causes of illness and death in tropical regions especially in Africa. The main parasitic diseases include leishmaniasis, filariasis, malaria, river blindness, Chagas disease and schistosomiasis. With the absence of vaccines, treatment relies mainly on chemotherapy hence the need for efficacious and safe medicines. Many of the medicines currently used have low efficacy and cause side effects. Some are also being lost to drug resistance. To address the inadequacy of treatment options for infectious diseases, a number of initiatives have been started to promote drug discovery and development in Africa. In parallel they have been collaboration between African institutions and leading pharmaceutical companies as well as other relevant R & D organizations. This has led to the need to modernize African approaches to drug discovery and development with respect to the integration of medicinal chemistry, pharmacology and pharmacokinetics as reflected in the processes of Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET). However, scientific and technological expertise in pharmacokinetics for drug discovery is under developed in Africa.
- 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 tetrahydrocannabinol, cannabidiol and cannabinol content of cannabis confiscated by the South African Police Service's Forensic Laboratories from various regions of South Africa(2014) Londt, Rolanda Sabrina; Smith, PeterIncludes abstract. Includes bibliographical references.