12 research outputs found
Population pharmacokinetics of terizidone and cycloserine in patients with drugresistant tuberculosis
Doctor Pharmaceuticae - DPharmIntroduction: Drug-resistant tuberculosis remains a major world health problem and
one of the leading cause of death worldwide. Despite adequate adherence to antituberculosis
drugs by patients, the emergence of drug-resistance tuberculosis still
occurs. This fact implies other factors leading to the emergence of resistant strains of
Mycobacterium tuberculosis. A multidrug treatment regimen, which may consist of five
to seven different drugs including terizidone, is used in the treatment of drugresistance
tuberculosis. Terizidone is part of the multidrug regimen whose
pharmacokinetics is scarce in literature and plasma concentration profile unknown.
Two molecules of cycloserine joined by terephtalaldehyde moiety makes up a
molecule of terizidone, which is thought to undergo complete metabolism into
cycloserine in vivo. Additionally, the current literature report that terizidone and
cycloserine can be used interchangeably as they are thought to be equivalent. The
aim of this thesis was first to develop and validate bioanalytical methods for
determination of terizidone and cycloserine in patientsâ plasma samples. Secondly, to
model population pharmacokinetics of terizidone and cycloserine. Thirdly, to
determine the amount of cycloserine resulting from metabolism of terizidone
ANTIMICROBIAL ACTIVITY AND POTENCY OF CASSIA ABBREVIATA OLIV STEM BARK EXTRACTS
Objective: To evaluate the potential antimicrobial activity and relative potency of aqueous and organic extracts of Cassia abbreviata Oliv stem bark against clinical isolates of Neisseria gonorrhoeae (NG), Pseudomonas aeruginosa (PA), Klebsiella pneumoniae (KP) and Candida albicans (CA).Methods: Six extracts of Cassia abbreviata Oliv stem bark were prepared as follows: Four extracts were prepared following Soxhlet extraction procedure using ethanol, water, trichloromethane (TCM) and dichloromethane (DCM)+ethanol (1:1) as solvents, respectively. Two extracts were prepared by soaking the powdered stem bark in ethanol and water, respectively, and subjected to mechanical shaking for 8 hours. Antimicrobial activities and minimum inhibitory concentrations (MIC) of extracts were evaluated in-vitro using agar well diffusion assay.Results: All extracts except TCM were active against NG and PA with an average MIC of 78.8 Ă”g/ml. The cold aqueous extract had a lowest MIC (46.88 Ă”g/ml) against PA, whereas both hot and cold ethanol extracts had a lowest MIC of 46.88 Ă”g/ml against NG. Only hot extracts (ethanol, DCM+ethanol and TCM) were active against KP with a lowest MIC of 46.88 Ă”g/ml of TCM extract. Both extracts of cold ethanol and DCM+ethanol were active against CA with cold ethanol extract having a lower MIC of 93.75 Ă”g/ml compared with DCM+ethanol.Conclusion: There were variations in in-vitro antimicrobial activities (microbial growth inhibition) of Cassia abbreviata Oliv stem bark extracts which depended on the solvent used. Organic extracts were more potent against NG, PA, KP and CA compared with aqueous extracts.Ă
Amount of cycloserine emanating from terizidone metabolism and relationship with hepatic function in patients with drug resistant tuberculosis
The dosing of cycloserine and terizidone is the same, as both drugs are considered equivalent
or used interchangeably. Nevertheless, it is not certain from the literature that these drugs are interchangeable. Therefore,
the amount of cycloserine resulting from the metabolism of terizidone and the relationship with hepatic function were
determined. This prospective clinical study involved 39 patients with drug-resistant tuberculosis admitted for an intensive
phase of treatment. Cycloserine pharmacokinetic parameters for individual patients, like area under the curve (AUC), clearance (CLm/F), peak concentration (Cmax) and trough concentration (Cmin), were calculated from a previously validated joint
population pharmacokinetic model of terizidone and cycloserine. Correlation and regression analyses were performed for
pharmacokinetic parameters and unconjugated bilirubin (UB), conjugated bilirubin (CB), albumin, the ratio of aspartate
transaminase to alanine aminotransferase (AST/ALT), or binding afnity of UB to albumin (Kaf), using R statistical software
version 3.5.3
Steadyâstate population pharmacokinetics of terizidone and itsmetabolite cycloserine in patients with drugâresistanttuberculosis
Despite terizidone being part of the secondâline recommended drugs fortreatment of drugâresistant tuberculosis (DRâTB), information on its pharmacokineticsis scarce. The aim of this study was to describe the steadyâstate population pharma-cokinetics (PPK) of terizidone and its primary metabolite cycloserine in patients withDRâTB and determine the effect of patient characteristics. This clinical study involved 39 adult DRâTB patients admitted toBrewelskloof Hospital in Cape Town, South Africa for intensive treatment phase.Blood samples were collected at predose and 0.5, 1, 2, 3, 3.5, 4, 8, 16 and 24 hoursafter drug administration. The estimation of PPK parameters was performed usingnonlinear mixedâeffects modelling software Monolix 2018R1. Freeâfat mass was usedto perform allometric scaling on disposition parameters
Associations between plasma tenofovir concentration and renal function markers in HIV-infected women
Background: Tenofovir disoproxil fumarate (TDF) has been associated with kidney tubular dysfunction and reduced renal function. Limited studies were performed in Europe and Asia that related plasma tenofovir (TFV) concentration with renal function; no such studies to date have been performed on Africans.Objective: To investigate the correlation between plasma tenofovir (TFV)Â concentration and certain renal function markers in HIV-infected women on TDF antiretroviral therapy (ART). These markers were also compared to a HIV-uninfected control group.Methods: HIV-infected women (n = 30) on TDF-based ART were matched with 30 controls for age and body mass index. Renal markers analysed were estimated glomerular filtration rate (eGFR), creatinine clearance (CrCl), serum creatinine, albuminuria, glucosuria, serum urea, serum uric acid, urine sodium and maximum tubular reabsorption of phosphate. Baseline eGFR and CrCl data were obtained retrospectively for the HIV-infected women. Plasma TFV was assayed using a validated HPLC-MS/MS method. Stepwise regression, MannâWhitney test, unpaired and paired t-tests were applied in the statistical analyses.Results: TFV concentration was independently associated with albuminuria (adjusted r2 = 0.339; p = 0.001) in HIV-infected women. In the adjusted (weight) analysis, eGFR (p = 0.038), CrCl (p = 0.032) and albuminuria (p = 0.048) were significantly higher in HIV-infected compared to the uninfected women, but eGFR was abnormally high in HIV-infected women. Both eGFR (p < 0.001) and CrCl (p = 0.008) increased from baseline to follow-up in HIV-infected women.Conclusion: Plasma TFV concentration was associated with increased albuminuria in HIVinfected women in this sub-study. Both eGFR and CrCl were increased in HIV-infected women from baseline. These findings should be confirmed in larger studies, and hyperfiltration in HIV-infected women warrants further investigation
Parental reporting of adverse drug reactions in South Africa: An online survey
The high incidence of adverse drug reactions (ADRs) in children is of global
concern. Enhancing the reporting of ADRs could contribute to making safer medicines
available to children.To assess parentsâ awareness of reporting ADRs and their knowledge on the reporting
procedures in South Africa.The questionnaire was completed voluntarily by 206 respondents. The majority of
participants (70.9%) were aware of the term ADR. Significant associations between not being
aware of the term ADR and single marital status, lower education level, not having private
medical aid and accessing public clinics for medical services were found. The majority
(66.5%) of participants did report an ADR to a healthcare professional whilst only 15%
reported it to a product manufacturer. More than half of the participants (58.7%) knew how
to report ADRs whilst 72.8% knew what type of ADRs to report. Almost a third (32.5%) did
not know where more information on ADR reporting could be found or how ADRs could be
reported (31.5%
Assessment of Vancomycin Pharmacokinetics and Dose Regimen Optimisation in Preterm Neonates
The pharmacokinetics of vancomycin, a drug used for the treatment of methicillin-resistant Staphylococcus
aureus (MRSA), varies between paediatric and adult patients.
The objective of this study was to assess the pharmacokinetics of vancomycin in preterm neonates and determine
the optimum dose regimen
hERG, Plasmodium Life Cycle, and Cross Resistance Profiling of New Azabenzimidazole Analogues of Astemizole
Toward addressing the cardiotoxicity liability associated with the antimalarial drug astemizole (AST, hERG IC50 = 0.0042 ÎŒM) and its derivatives, we designed and synthesized analogues based on compound 1 (Pf NF54 IC50 = 0.012 ÎŒM; hERG IC50 = 0.63 ÎŒM), our previously identified 3-trifluoromethyl-1,2,4-oxadiazole AST analogue. Compound 11 retained in vitro multistage antiplasmodium activity (ABS PfNF54 IC50 = 0.017 ÎŒM; gametocytes PfiGc/PfLGc IC50 = 1.24/1.39 ÎŒM, and liver-stage PbHepG2 IC50 = 2.30 ÎŒM), good microsomal metabolic stability (MLM CLint < 11 ÎŒL·min-1·mg-1, EH < 0.33), and solubility (150 ÎŒM). It shows a âŒ6-fold and >6000-fold higher selectivity against human ether-ĂĄ-go-go-related gene higher selectively potential over hERG relative to 1 and AST, respectively. Despite the excellent in vitro antiplasmodium activity profile, in vivo efficacy in the Plasmodium berghei mouse infection model was diminished, attributable to suboptimal oral bioavailability (F = 14.9%) at 10 mg·kg-1 resulting from poor permeability (log D7.4 = â0.82). No cross-resistance was observed against 44 common Pf mutant lines, suggesting activity via a novel mechanism of action.</p
hERG, Plasmodium life cycle, and cross resistance profiling of new azabenzimidazole analogues of astemizole
SUPPLEMENTARY INFORMATION : Experimental procedures and characterization data of synthetic intermediates (5aâ5f, 6aâ6f, 13, and 15) and target compounds (7â12 and 15); biochemical assay protocols, including solubility and cross-resistance studies; H NMR spectra of representative target compounds.Please read abstract in the article.The University of Cape Town (UCT), South African Medical Research Council, the South African Research Chairs Initiative (SARChI) of the Department of Science and Innovation (DSI) administered through the South African National Research Foundation (NRF), the Brazilian National Council for Scientific and Technological Development, Proep-Fiocruz Program (Brazil), the Neville Isdell Chair in African-centric Drug Discovery and Development, and Neville Isdell for generously funding the Chair.http://pubs.acs.org/journal/amclcthj2024BiochemistryGeneticsMicrobiology and Plant PathologyUP Centre for Sustainable Malaria Control (UP CSMC)SDG-03:Good heatlh and well-bein
A pilot investigation on plasma tenofovir levels and possible side effects in HIV-infected women
MSc (Pharmacology), North-West University, Potchefstroom Campus, 2015Tenofovir disoproxil fumarate (TDF) is a nucleotide reverse transcriptase inhibitor and a prodrug of tenofovir (TFV). It is the currently recommended first line combination treatment of human immunodeficiency virus (HIV) infection in adults. Various clinical studies have associated treatment with a TDF-containing antiretroviral therapy (ART) regimen with reduced bone mineral density (BMD) and renal dysfunction. Hardly any studies to date have correlated plasma TFV concentration with markers of renal function and bone turnover (BTM). This knowledge is also unavailable in the South African public health care system. Hence, the correlations between plasma TFV concentration and renal function markers and BTM in HIV-infected women were investigated. Renal function markers and BTM in HIV-infected women were compared with those in HIV-uninfected control women. A pilot cross-sectional sub-study within the Prospective Urban and Rural Epidemiology (PURE) South Africa study was conducted. Sixty women participated, of which 30 HIV-infected women were matched for age and body mass index with 30 HIV-uninfected ones. Ethics approval was obtained from the North-West University, Human Research Ethics committee (NWU-00016-10-A1) on 12 April 2013 to conduct this sub-study and the North West Department of Health, Mmabatho on 08 August 2013 to access patient health information. A validated high-performance liquid chromatography tandem mass spectrometry method was developed to analyse TFV in plasma. Renal markers measured were the estimated glomerular filtration rate (eGFR), creatinine clearance (CrCl), albuminuria, serum creatinine (SCr), serum urea, serum uric acid, glucosuria, urine sodium (UNa) and maximum tubular reabsorption of phosphate (TmPO4/GFR). The BTM markers measured included C-terminal telopeptide (CTx), alkaline phosphatase (ALP), parathyroid hormone (PTH), total vitamin D (VitD), serum calcium (SrCa), serum phosphate (SrP) and BMD. BMD was assessed using the DTX-200 peripheral DXA system (Osteometer MediTech, Hawthorn, California, USA). Renal and bone markers were analysed on ElecsysÂź 2010 and COBAS INTERGRAÂź 400 plus (Roche Diagnostics, Switzerland). Baseline data for HIV-infected participants with regard to CD4+ cell count, SCr prior to TDF initiation, time since TDF initiation, weight prior to TDF initiation and time since HIV diagnosis were collected retrospectively from participantsâ public health care files. Statistical analyses applied were linear regression, analysis of covariance, the Mann-Whitney U test, paired t-test and unpaired t-test. IBMÂź SPSSÂź Statistics software 22 was used to perform all the statistical analyses. The median and interquartile range of plasma TFV concentration was 113 (74-139.4) ng/mL (n=25) and no TFV was detected in five participantsâ plasma. Adjusted analyses showed TFV concentration to be associated with albuminuria (adjusted r2 = 0.339; p = 0.001). Values of CrCl, eGFR and albuminuria (p = 0.032; p = 0.038; p = 0.048, respectively) were significantly higher in HIV-infected women compared to HIV-uninfected women. CrCl [112 (84-137) mL/min] and eGFR [134 (93-153) mL/min/1.73m2] values were abnormally high in HIV-infected women. There was also an increase in both CrCl and eGFR (p = 0.008; p < 0.001, respectively) from baseline to median follow-up of 16.6 (8.8-23.4) months in HIV-infected women. At a TFV plasma concentration of â„ 120 ng/mL, CTx and ALP correlated positively (r = 0.704; p = 0.016). ALP (112 ± 28 U/L; p < 0.001), CTx (0.68 ± 0.4 ng/mL; p = 0.027) and PTH (56.3 ± 32 pg/mL; p = 0.050) were higher in HIV-infected women compared to HIV-uninfected women. CD4+ cell count increased from baseline to follow-up in HIV-infected women (+250 cells/mm3; p = 0.001). In HIV-infected women on a TDF-based regimen, TFV plasma concentration is associated with an increase in albuminuria, while perturbations in BTM equilibrium occur at â„ 120 ng/mL of TFV plasma concentration. Abnormally higher CrCl and eGFR are present in HIV-infected women, seen as glomerular hyperfiltration compared with HIV-uninfected women. There was immunological improvement with TDF-based ART in HIV-infected women. Longitudinal studies with larger sample sizes are needed to confirm these findings.Master