Browsing by Department "Division of Clinical Pharmacology"
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- ItemOpen AccessA comparison of self-report and antiretroviral detection to inform estimates of antiretroviral therapy coverage, viral load suppression and HIV incidence in Kwazulu-Natal, South Africa(2017) Huerga, Helena; Shiferie, Fisseha; Grebe, Eduard; Giuliani, Ruggero; Farhat, Jihane Ben; Van Cutsem, Gilles; Cohen, KarenAccurately identifying individuals who are on antiretroviral therapy (ART) is important to determine ART coverage and proportion on ART who are virally suppressed. ART is also included in recent infection testing algorithms used to estimate incidence. We compared estimates of ART coverage, viral load suppression rates and HIV incidence using ART self-report and detection of antiretroviral (ARV) drugs and we identified factors associated with discordance between the methods.
- ItemOpen AccessA pharmacokinetic and antimalarial efficacy evaluation of pyridodibemequines and their metabolites(2021) Redhi, Devasha; Wiesner, Lubbe; Egan, Timothy JohnThe recurring challenge of the emergence of drug resistance necessitates the continual development of improved antimalarial treatments, which can target parasite strains that display reduced susceptibility towards current therapy. Consequently, a novel series of dual functioning pyridodibemequine (PDBQ) compounds were designed with the intention of reversing resistance in chloroquine-resistant (CQR) strains of Plasmodium falciparum. These hybrid molecules integrate a 4-amino-7-chloroquinoline antiplasmodial core with a modified dibenzylmethylamine side chain, which interacts with the CQR mutant P. falciparum chloroquine resistance transporter (PfCRT) to hinder the efflux of chloroquine (CQ) from its site of action, thereby reversing CQ resistance. The parent compounds of the PDBQ series, which differ in the ortho-, meta-, and para-orientation of the dibenzylmethylamine side chain, displayed favourable in vitro potency against chloroquine-sensitive (CQS) and CQR strains of P. falciparum; however, they were shown to be metabolically labile. Structure elucidation demonstrated that all formed PDBQ metabolites retained the 4-amino-7-chloroquinoline pharmacophore of the parent. Thus, the major metabolites, M1 and M2, generally conserved the in vitro antimalarial activity and selectivity of the parent compounds. Mechanistic studies revealed that the antiplasmodial activity of the PDBQ parent compounds and major metabolites primarily results from the inhibition of haemozoin formation, culminating in a toxic accumulation of ferriprotoporphyrin IX. The parents and major metabolites exhibited minimal toxicity against a mammalian cell line, and the metabolites are proposed to display reduced systemic toxicity, and human ether-a-go-go-related gene liability compared to the parent compounds. Furthermore, the major metabolites generally exhibited similar or improved in vitro solubility, permeability, lipophilicity, and metabolic stability compared to the parent compounds. Therefore, given their favourable in vitro characteristics, the major active metabolites of each parent PDBQ compound were further evaluated in this project to determine their potential as early preclinical antimalarial lead candidates. The proof of concept study presented herein investigated the in vivo pharmacokinetics (PK) of the PDBQ series of parents and major metabolites in a healthy murine model to allow the rational selection of candidates to be evaluated for their in vivo antimalarial efficacy and PK in a P. falciparum-infected murine model. For the PK studies in healthy and malaria-infected mice, analyte detection from whole blood was achieved using high-performance liquid chromatography coupled to tandem mass spectrometry. The bioanalytical methods were developed and partially validated based on a fit-for-purpose approach, which ensured that the generated PK concentration data was reliable and accurate. Lastly, given the significance of combination therapy in delaying the onset of drug resistance, fixed-dose ratio isobologram analyses were performed to probe the potential of the lead candidates to be used synergistically with an antimalarial partner drug possessing a distinct mechanism of action to haemozoin inhibition. Additionally, the ability of the lead candidates to reverse CQ resistance was evaluated in a CQR strain of P. falciparum. A comparative PK study was performed in a healthy murine model to determine whether the parent PDBQ compound should be used as a strategy to deliver the active metabolites or whether the active major metabolite should be directly administered. This was achieved by oral administration of the parent PDBQ compound and subsequent quantification of the parent compound and formation of the major metabolites. In addition, each pre-synthesised major metabolite was orally administered, at the equivalent parent dose, to characterise the PK profile of the individual active metabolite. These PK studies revealed that the overall oral exposure of the antimalarial pharmacophore was markedly greater after direct administration of the preformed metabolite compared to the cumulative oral exposure of the parent and formed metabolites after administration of the parent PDBQ compound. Furthermore, the metabolites attained higher maximal concentrations and maintained circulating concentrations which favourably exceeded their respective in vitro half-maximal inhibitory concentration at 24 h post-oral administration compared to the parent compounds at the equivalent oral dose. These findings substantiated the direct administration of the preformed PDBQ major metabolite over the parent compound. From the series of PDBQ metabolite derivatives, compounds 43M1 and 47M1 displayed the highest maximal concentrations of 8 ± 1 and 9.4 ± 0.5 μM, respectively and the greatest oral exposures of 62 ± 3 and 93 ± 9 µM.h, respectively, after single 20 mg/kg oral administrations of either 43M1 or 47M1. Given their encouraging PK profiles, 43M1 and 47M1 were selected to progress to the subsequent phase of the study which evaluated their in vivo antimalarial efficacy and pharmacokinetic/pharmacodynamic (PK/PD) relationship in a P. falciparum-infected humanised murine model. 43M1 and 47M1 were efficacious against asexual intraerythrocytic P. falciparum infection in humanised mice, where both compounds displayed a 98% reduction in parasitaemia after 4 consecutive daily oral administrations of 20 mg/kg of either 43M1 or 47M1 compared to the untreated control. The PK/PD analysis revealed dose-dependent reductions in parasitaemia; and the doses required to produce 90% of the maximal parasiticidal response (ED90) were 12 and 7.7 mg/kg for 43M1 and 47M1, respectively. Additionally, the oral exposures required to achieve the effect at the ED90 were 6.2 and 18.6 µM.h for 43M1 and 47M1, respectively. 43M1 or 47M1 demonstrated overall in vitro antimalarial synergy with dihydroartemisinin or atovaquone and additivity with methylene blue in CQS and CQR strains of P. falciparum. 43M1 or 47M1 with mefloquine or lumefantrine displayed in vitro antimalarial synergy in a CQS strain of P. falciparum; however, in a CQR strain, antagonism and additivity were displayed with mefloquine and lumefantrine, respectively. Additionally, 43M1 and 47M1 were unable to potentiate the in vitro antiplasmodial activity of CQ in a CQR strain of P. falciparum which suggested that, unlike the parent PDBQ compound, the metabolite did not possess the ability to reverse CQ resistance. The promising in vivo antimalarial efficacy of 43M1 and 47M1 against P. falciparum and their prospective in vitro antimalarial synergy with dihydroartemisinin and atovaquone underlines the potential of 43M1 and 47M1 for further development as preclinical antimalarial candidates.
- ItemOpen AccessAGREE to disagree: critical appraisal and the publication of practice guidelines(2014) Wiseman, Roger; Cohen, Karen; Gray, Andy; Jamaloodien, Khadija; Kredo, Tamara; Miot, Jacqui; Parrish, Andy; Taylor, Bettina; Blockman, MarcFaced by an explosion in available evidence for multiple new treatments, busy clinicians value guidelines that are clear, reliable, unbiased and locally applicable. Finding them can be difficult, however. The science of guideline development has moved rapidly in the past decade, resulting in a more robust and systematic process. However, just as the language of evidence-based medicine can be subverted to sound convincing while hiding errors and biases, so too guidelines may look convincing but lack many of the elements needed to ensure quality of care. In particular, the pharmaceutical and health technology industries are intensely aware of the marketing potential offered by widely disseminated and ostensibly neutral documents that ultimately influence medical practice.
- ItemOpen AccessAntibacterial and antimycobacterial activities of South African Salvia species and isolated compounds from S. chamelaeagnea(2007) Seaman, T; Kamatou, G P P; Van Vuuren, S F; Van Heerden, F R; Viljoen, A MExtracts of 16 South African Salvia species commonly used in traditional medicine to treat various microbial infections were investigated for in vitro antibacterial and antimycobacterial activities using the micro-dilution and respiratory BACTEC method, respectively. The micro-organisms tested include two Gram-positive (Staphylococcus aureus and Bacillus cereus); two Gram-negative (Escherichia coli and Klebsiella pneumoniae) bacterial strains and the common pathogen responsible for tuberculosis, Mycobacterium tuberculosis. Extracts of the majority of species exhibited moderate to good antibacterial activity with minimum inhibitory concentration (MIC) values ranging from 0.03 to 8.00 mg/ml. Promising activity was observed against M. tuberculosis (MIC ≤ 0.50 mg/ml) with S. radula, S. verbenaca and S. dolomitica displaying the most favourable activity (MIC: 0.10 mg/ml). The antibacterial bioassay-guided fractionation of S. chamelaeagnea resulted in the isolation of four compounds: carnosol, 7-O-methylepirosmanol, oleanolic acid and its isomer ursolic acid as the active principles against S. aureus. The in vitro antibacterial and antimycobacterial activities may support the use of Salvia species in traditional medicine to treat microbial infections.
- ItemOpen AccessAntidiabetic activity of Schkuhria pinnata – Biological screening, PK analysis and mode of actionSewnarain, Prenitha; Smith, P; Muller, C J FThe increasing reliance on drugs from natural sources has led to the development of several drugs from traditional plants which are present in abundance in Southern Africa. With the rapid increase of incidence of type 2 diabetes in South Africa with potentially devastating effects on healthcare, the need for alternative therapeutics is a priority. In this study, Schkuhria pinnata (Lam.) Kuntze was investigated for its antidiabetic potential. Initial screening of two different solvent extracts of S. pinnata identified an aqueous extract that lowered blood glucose concentrations in a hyperglycaemic streptozotocin-induced diabetic rat. The classical bioassay approach was followed by using different solvents, drying processes and fractionation in order to produce the most active extract and attempt to isolate an active compound(s). An aqueous freeze dried extract was found to be the most active at stimulating glucose uptake activity in C2C12 and Chang cells. Fractionation of this extract in an attempt to identify the active compound yielded a novel crystalline compound 1 by NMR analysis. Screening for bioactivity of the extract and compound 1 using C2C12 muscle and Chang cells revealed that both extract and compound 1 were biologically active, however the activity of the aqueous extract was more significant overall. A butanone/pentane extract prepared for possible commercialization purposes was also shown to be active in vitro. To establish antidiabetic activity, the aqueous freeze dried extract, butanone/pentane extract and the enriched compound 1 fraction were tested in a streptozotocin (STZ) diabetic rat model showing hypoglycaemic effects for the aqueous freeze dried extract. Messenger RNA and protein studies on C2C12 muscle cells revealed that the aqueous freeze dried extract and compound 1 enhanced insulin receptor, GLUT-4, glycogen synthase, pyruvate kinase and pyruvate carboxylase expression, suggestive of an insulin mimetic mode of action, while the butanone/pentane extract enhanced adenosine monophosphate-activated kinase (AMPK) protein expression by a non-insulin dependent mechanism. A pharmacokinetic study (PK) established bioavailability of compound 1 following oral administration of the extracts, but not from the compound 1 enriched fraction. From this study, the traditional use of S. pinnata has been scientifically validated as having antidiabetic properties. In vitro and in vivo bioassays, confirmed that an aqueous freeze dried extract which was prepared as per the traditional method had the most promising antidiabetic iii activity. Compound 1 isolated from an active fraction was proven to be almost as effective as the parent extract in in vitro studies. This compound could therefore be the major active ingredient responsible for the uptake of glucose in cells and the hypoglycaemic activity in vivo. In this study, the antidiabetic activities together with the mechanism of action of S. pinnata extracts and compound 1 were elucidated. The highlight of the study was the identification of a bioactive novel chemical entity (NCE) compound 1 (identified as 2-(2-{[(2E)-4-hydroxy2-(hydroxymethyl)but-2-enoyl]oxy}-4,7-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)prop-2- enoic acid) isolated from an active fraction of S. pinnata that was proven to be almost as effective as the parent extract in in vitro studies. This compound could therefore be the major active ingredient responsible for the uptake of glucose in cells and the hypoglycaemic activity in vivo. The cellular mechanism of action of the S. pinnata extracts and compound 1 demonstrated both insulin mimetic and non-insulin dependent mechanisms (AMPK) in C2C12 muscle cells. Further research in the form of preclinical and clinical trials need to be undertaken to make this extract or biologically active compound available as a herbal remedy or nutraceutical therapeutic for diabetes. To achieve this; safety, efficacy and mode of action studies will have to be established. The synthesis of compound 1 and/or analogues should also be investigated as an antidiabetic drug candidate.
- 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 AccessAntimycobacterial activity of the red algae gelidium pristoides, plocamium corallorhiza and polysiphonia virgata(2006) Saravanakumar, Denise; Folb, Peter I; Smith, Peter J; Campbell, William EIn 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.
- ItemOpen AccessAntiplasmodial activity, in vivo pharmacokinetics and anti-malarial efficacy evaluation of hydroxypyridinone hybrids in a mouse model(2015) Dambuza, Ntokozo S; Smith, Peter; Evans, Alicia; Norman, Jennifer; Taylor, Dale; Andayi, Andrew; Egan, Timothy; Chibale, Kelly; Wiesner, LubbeBackgroundDuring the erythrocytic stage in humans, malaria parasites digest haemoglobin of the host cell, and the toxic haem moiety crystallizes into haemozoin. Chloroquine acts by forming toxic complexes with haem molecules and interfering with their crystallization. In chloroquine-resistant strains, the drug is excluded from the site of action, which causes the parasites to accumulate less chloroquine in their acid food vacuoles than chloroquine-sensitive parasites. 3-Hydroxylpyridin-4-ones are known to chelate iron; hydroxypyridone-chloroquine (HPO-CQ) hybrids were synthesized in order to determine whether they can inhibit parasites proliferation in the parasitic digestive vacuole by withholding iron from plasmodial parasite metabolic pathway.MethodsTwo HPO-CQ hybrids were tested against Plasmodium falciparum chloroquine-sensitive (D10 and 3D7) and -resistant strains (Dd2 and K1). The pharmacokinetic properties of active compounds were determined using a mouse model and blood samples were collected at different time intervals and analysed using LC–MS/MS. For in vivo efficacy the mice were infected with Plasmodium berghei in a 4-day Peters’ test. The parasitaemia was determined from day 3 and the course of the infection was followed by microscopic examination of stained blood films every 2–3days until a rise in parasitaemia was observed in all test subjects.ResultsIC50 values of the two compounds for sensitive and resistant strains were 0.064 and 0.047µM (compound 1), 0.041 and 0.122µM (compound 2) and 0.505 and 0.463µM (compound 1), 0.089 and 0.076µM (compound 2), respectively. Pharmacokinetic evaluation of these compounds showed low oral bioavailability and this affected in vivo efficacy when compounds were dosed orally. However, when dosed intravenously compound 1 showed a clearance rate of 28ml/min/kg, an apparent volume of distribution of 20l/kg and a half-life of 4.3h. A reduction in parasitaemia was observed when compound 1 was dosed intravenously for four consecutive days in P. berghei-infected mice. However, a rise in parasitaemia levels was observed on day 6 and on day 9 for chloroquine-treated mice.ConclusionThe hybrid compounds that were tested were able to reduce parasitaemia levels in P. berghei-infected mice when dosed intravenously, but parasites recrudesced 24h after the administration of the least dose. Despite low oral bioavailability, the IV data obtained suggests that further structural modifications may lead to the identification of more HPO-CQ hybrids with improved pharmacokinetic properties and in vivo efficacy.
- ItemOpen AccessThe antiplasmodial, toxicity and pharmacokinetic properties of synthetic derivatives of the natural product Curcumin(2008) Okalebo, Faith Apolot; Smith, Peter J; Chibale, Kelly; Guantai, Anastasia NIncludes bibliographical references.
- ItemOpen AccessAntiretroviral therapy adherence and effectiveness in a private sector disease management programme in Southern Africa(2008) Nachega, Jean B; Maartens, GaryIncludes abstract. Includes bibliographical references.
- ItemOpen AccessArtesunate and amodiaquine : tolerability and drug interaction study in healthy normal volunteers(2005) Orrell, Catherine; Smith, PeterIncludes bibliographical references.
- ItemOpen AccessAssessment of quality of obstetric care in Zimbabwe using the standard primipara(BioMed Central, 2018-06-04) Guzha, Bothwell T; Magwali, Thulani L; Mateveke, Bismark; Chirehwa, Maxwell; Nyandoro, George; Munjanja, Stephen PBackground To improve maternity services in any country, there is need to monitor the quality of obstetric care. There is usually disparity of obstetric care and outcomes in most countries among women giving birth in different obstetric units. However, comparing the quality of obstetric care is difficult because of heterogeneous population characteristics and the difference in prevalence of complications. The concept of the standard primipara was introduced as a tool to control for these various confounding factors. This concept was used to compare the quality of obstetric care among districts in different geographical locations in Zimbabwe. Methods This was a substudy of the Zimbabwe Maternal and Perinatal Mortality Study. In the main study, cluster sampling was done with the provinces as clusters and 11 districts were randomly selected with one from each of the nine provinces and two from the largest province. This database was used to identify the standard primipara defined as; a woman in her first pregnancy without any known complications who has spontaneous onset of labour at term. Obstetric process and outcome indicators of the standard primipara were then used to compare the quality of care between rural and urban, across rural and across urban districts of Zimbabwe. Results A total of 45,240 births were recruited in the main study and 10,947 women met the definition of standard primipara. The maternal mortality ratio (MMR) and the perinatal mortality rate (PNMR) for the standard primiparae were 92/100000 live births and 15.4/1000 total births respectively. Compared to urban districts, the PNMR was higher in the rural districts (11/1000 total births vs 19/ 1000 total births, p < 0.001). In the urban to urban and rural to rural districts comparison, there were significant differences in most of the process indicators, but not in the PNMR. Conclusions The study has shown that the standard primipara can be used as a tool to measure and compare the quality of obstetric care in districts in different geographical areas. There is need to explore further how the quality of obstetric care can be improved in rural districts of Zimbabwe.
- ItemOpen AccessAssessment of therapeutic responses to gametocytocidal drugs in Plasmodium falciparum malaria(2014-12-09) White, Nicholas J; Ashley, Elizabeth A; Recht, Judith; Delves, Michael J; Ruecker, Andrea; Smithuis, Frank M; Eziefula, Alice C; Bousema, Teun; Drakeley, Chris; Chotivanich, Kesinee; Imwong, Mallika; Pukrittayakamee, Sasithon; Prachumsri, Jetsumon; Chu, Cindy; Andolina, Chiara; Bancone, Germana; Hien, Tran T; Mayxay, Mayfong; Taylor, Walter R; von Seidlein, Lorenz; Price, Ric N; Barnes, Karen I; Djimdé, Abdoulaye; ter Kuile, Feiko; Gosling, Roly; Chen, Ingrid; Dhorda, Mehul J; Stepniewska, Kasia; Guérin, Philippe; Woodrow, Charles J; Dondorp, Arjen M; Day, Nicholas P; Nosten, Francois HAbstract Indirect clinical measures assessing anti-malarial drug transmission-blocking activity in falciparum malaria include measurement of the duration of gametocytaemia, the rate of gametocyte clearance or the area under the gametocytaemia-time curve (AUC). These may provide useful comparative information, but they underestimate dose-response relationships for transmission-blocking activity. Following 8-aminoquinoline administration P. falciparum gametocytes are sterilized within hours, whereas clearance from blood takes days. Gametocytaemia AUC and clearance times are determined predominantly by the more numerous female gametocytes, which are generally less drug sensitive than the minority male gametocytes, whereas transmission-blocking activity and thus infectivity is determined by the more sensitive male forms. In choosing doses of transmission-blocking drugs there is no substitute yet for mosquito-feeding studies.
- 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 AccessAssociation 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, GaryAbstract 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.
- ItemOpen AccessBioassay-guided fractionation of Artemisia afra for in vitro antimalarial activity against Plasmodium falciparum(1997) Abrahams, Meryl Arlene; Folb, Peter I; Gammon, David WWith the increase in recent years in the prevalence of malaria, and in drug resistance of Plasmodium falciparum, there has been much interest in natural plant products for new antimalarials with novel modes of action against Plasmodium. Artemisinin or Qinghaosu is one such antimalarial isolated from a Chinese herb, Anemisia annua (Asteraceae) and it is currently undergoing phase I and II clinical trials. The Southern African species, Artemisia afra (African wormwood, wildeals, lengana) is commonly used by local traditional healers for symptoms of malaria, in particular fever. Thus it seemed appropriate to investigate this species for antimalarial activity. Crude petroleum ether soxhlet extracts of Anemisia afra had demonstrated antimalarial activity against Plasmodium falciparum, FCR-3, cultured in vitro. The IC₅₀ values ranged from 5-13μg/ml. The extract from leaves and flowers was then screened against D10 (chloroquine-sensitive) and FAC8 (chloroquineresistant) P. falciparum, in vitro, with IC₅₀ values of 1.03μg/ml and l.5μg/ml respectively. This extract was fractionated by column chromatography using silica gel-60 and the fractions obtained were screened for antimalarial activity. The most active fraction had an IC₅₀ of 0.5μg/ml against D10 and FAC8. Using TLC and HPLC-UV analysis with pure artemisinin as a standard, no artemisinin could be detected in this fraction. This result was confirmed by thermospray LC-MS analyses. Purification of this fraction yielded ultimately a single pure compound; a clear colourless oil identified by MS and NMR analyses as hydroxydavanone. The compound was screened against a variety of P. falciparum strains with varying degrees of sensitivity and resistance to both chloroquine and mefloquine. Their sensitivity against artemisinin was also established. IC₅₀ values obtained for the isolated pure compound against P. falciparum ranged from 0.87 to 2.54μg/ml. The IC₅₀ values obtained for general cytotoxicity of the crude extract and isolated pure compound against RAT-I fibroblast cells were 34.78 ± 8.23 and 6.29 ± 0.95 μg/ml (n=4) respectively. Thus the crude extract and isolated pure compound exhibited a greater antimalarial than cytotoxic effect. Hence, there are implications for A. afra to be used as a phytomedicine for the treatment of malaria. In vivo studies are recommended for hydroxydavanone in order to fully assess its potential for clinical use.
- ItemOpen AccessThe biogenesis of erythropoietin during inflammation(1995) Leng, Henry Martin John; Folb, Peter I; Keraan, M E; Kidson, Sue HAnaemia frequently accompanies chronic inflammatory diseases like rheumatoid arthritis and cancer. It is postulated to result primarily from the suppression of erythropoiesis by inflammatory cytokines. A contributing factor could be the inhibition of erythropoietin synthesis which may also be mediated by cytokines. Erythropoietin is the hormone which regulates erythropoiesis. The aims of this project were to investigate whether cytokines can indeed suppress erythropoietin production, and to determine whether the erythropoietin response in experimental models of acute and chronic inflammation was appropriate for the associated anaemia. Macrophage-conditioned medium, interleukin-1β, interleukin-6, tumour necrosis factor-α, and neopterin were assayed for inhibition of erythropoietin synthesis by HepG2 cells in culture. All, except neopterin, effected dose-dependent reductions in the secretion of the hormone. Interleukin-1β and tumour necrosis factor-α down-regulated erythropoietin gene transcription, whereas interleukin-6 inhibited a post-transcriptional process. Rats with acute inflammation developed a mild anaemia which evoked an increase in their serum levels of erythropoietin. The serum erythropoietin levels were optimal, since rats with acute inflammation and severe phenylhydrazine-induced anaemia did not have lower levels of the hormone than controls with a similar degree of anaemia, but without acute inflammation. Erythropoietin is, therefore, not an acute phase reactant. Mice with cancer developed a progressive anaemia which was not due to bone marrow invasion by tumour cells. During the first fourteen days after inoculating them with cancer cells, the mice responded by increasing their serum levels of erythropoietin as the anaemia worsened. The erythropoietin response was appropriate when compared to mice with the same degree of phenylhydrazine-induced anaemia. Erythropoietin levels measured in mice with tumours older than fourteen days were significantly lower than those of control mice with the same degree of experimental anaemia. These animals were very cachectic, suggesting that a blunted erythropoietin response may depend on disease activity.
- ItemOpen AccessC-reactive protein and procalcitonin to discriminate between tuberculosis, Pneumocystis jirovecii pneumonia, and bacterial pneumonia in HIV-infected inpatients meeting WHO criteria for seriously ill: a prospective cohort study(BioMed Central, 2018-08-14) Mendelson, Fiona; Griesel, Rulan; Tiffin, Nicki; Rangaka, Molebogeng; Boulle, Andrew; Mendelson, Marc; Maartens, GaryBackground Tuberculosis, bacterial community-acquired pneumonia (CAP), and Pneumocystis jirovecii pneumonia (PJP) are the three commonest causes of hospitalisation in HIV-infected adults. Prompt diagnosis and treatment initiation are important to reduce morbidity and mortality, but are hampered by limited diagnostic resources in resource poor settings. C-reactive protein (CRP) and procalcitonin have shown diagnostic utility for respiratory tract infections, however few studies have focussed on their ability to distinguish between tuberculosis, CAP, and PJP in HIV-infected inpatients. Methods We evaluated the diagnostic accuracy of CRP and procalcitonin, compared with composite reference standards, to discriminate between the three target infections in adult HIV-infected inpatients in two district level hospitals in Cape Town, South Africa. Participants were admitted with current cough and danger signs in accordance with the WHO algorithm for tuberculosis in seriously ill HIV-infected patients. Study clinicians were blinded to CRP and procalcitonin results. Results Two hundred forty-eight participants met study case definitions: 133 with tuberculosis, 61 with CAP, 16 with PJP, and 38 with mixed infection. In the 210 particpants with single infections the differences in median CRP and procalcitonin concentrations between the three infections were statistically significant, but distributions overlapped considerably. CRP and procalcitonin concentrations were highest in the CAP group and lowest in the PJP group. CRP and procalcitonin cut-offs with sensitivities of ≥90% were found for all three target infection pairs, but corresponding specificities were low. Highest receiver operating characteristic areas under the curve for CRP and procalcitonin were for PJP versus tuberculosis and PJP versus CAP (0.68 and 0.71, and 0.74 and 0.69 respectively). Conclusions CRP and procalcitonin showed limited value in discriminating between the three target infections due to widely overlapping distributions, but diagnostic accuracy was higher for discriminating PJP from CAP or tuberculosis. Our findings show limitations for CRP and procalcitonin, particularly for discriminiation of tuberculosis form CAP, however they may have greater diagnostic utility as part of a panel of biomarkers or in clinical prediction rules.