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 patients’ 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 µg/ml. The cold aqueous extract had a lowest MIC (46.88 µg/ml) against PA, whereas both hot and cold ethanol extracts had a lowest MIC of 46.88 µg/ml against NG. Only hot extracts (ethanol, DCM+ethanol and TCM) were active against KP with a lowest MIC of 46.88 µg/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 µg/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.Â

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

Steady‐state population pharmacokinetics of terizidone and itsmetabolite cycloserine in patients with drug‐resistanttuberculosis

Despite terizidone being part of the second‐line recommended drugs fortreatment of drug‐resistant tuberculosis (DR‐TB), information on its pharmacokineticsis scarce. The aim of this study was to describe the steady‐state population pharma-cokinetics (PPK) of terizidone and its primary metabolite cycloserine in patients withDR‐TB and determine the effect of patient characteristics. This clinical study involved 39 adult DR‐TB 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 mixed‐effects modelling software Monolix 2018R1. Free‐fat 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)  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, Mann–Whitney 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 parents’ 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 μM) and its derivatives, we designed and synthesized analogues based on compound 1 (Pf NF54 IC50 = 0.012 μM; hERG IC50 = 0.63 μM), our previously identified 3-trifluoromethyl-1,2,4-oxadiazole AST analogue. Compound 11 retained in vitro multistage antiplasmodium activity (ABS PfNF54 IC50 = 0.017 μM; gametocytes PfiGc/PfLGc IC50 = 1.24/1.39 μM, and liver-stage PbHepG2 IC50 = 2.30 μM), good microsomal metabolic stability (MLM CLint &lt; 11 μL·min-1·mg-1, EH &lt; 0.33), and solubility (150 μM). It shows a ∼6-fold and &gt;6000-fold higher selectivity against human ether-á-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 = −0.82). No cross-resistance was observed against 44 common Pf mutant lines, suggesting activity via a novel mechanism of action.</p

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 Elecsys® 2010 and COBAS INTERGRA® 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 participants’ 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. IBM® SPSS® 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 participants’ 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 ≥ 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 ≥ 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

Bone turnover markers in HIV-infected women on tenofovir-based antiretroviral therapy

Background: Tenofovir disoproxil fumarate (TDF) antiretroviral therapy is associated with disruption of the bone turnover process. Objectives: The objective of this study was to determine the association between tenofovir (TFV) plasma concentration and various bone turnover markers and compare these markers in HIV-infected women and HIV-uninfected controls. Method: A cross-sectional sub-study included 30 HIV-infected women on TDF and 30 HIV-uninfected matched participants. Serum calcium (SrCa), serum phosphate (SrP), C-terminal telopeptide (CTx), parathyroid hormone (PTH), alkaline phosphatase (ALP), C-reactive protein (CRP), vitamin D (VitD) and bone mineral density (BMD) were measured. Plasma TFV was assayed on HPLC-MS/MS. The statistical tests applied were Mann–Whitney test, unpaired t-test, analysis of covariance, regression and correlation analysis. Results: In HIV-infected women, no correlation existed between plasma TFV concentration and CTx, PTH, ALP, SrCa, SrP, VitD or BMD (p > 0.05). After adjusting for smoking and alcohol use, ALP (p 0.05). Conclusion: The results indicate possible increased bone turnover at higher TFV concentrations. The normal regular bone turnover processes in HIV-infected women on TDF therapy are altered. Larger studies are warranted to confirm these results