Research Articles (Clinical Pharmacology)
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- ItemInvestigating the pharmacokinetics of a grape seed-derived proanthocyanidin extract in healthy human subjects.(Stellenbosch : Stellenbosch University, 2024-12) Abdulla, Zohra Bibi; Petersen-Ross, Kelly; Kellermann, Tracy; Smith, Carine; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine. Division of Clinical Pharmacology.ENGLISH ABSTRACT: Introduction: Oxidative stress and inflammation have been implicated in the ageing phenotype associated with the development of non-communicable diseases (NCDs). Several pre-clinical and clinical studies have demonstrated the beneficial properties of grape seed-derived polyphenols in mediating oxidative stress. However, limited information on the bioavailability and pharmacokinetics of these products is available. This study consisted of the development and validation of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantify catechin, epicatechin and procyanidin B1 as constituents of a grape seed derived supplement, OxiprovinTM in human plasma. Subsequently, the method was applied to an early phase clinical trial investigating the pharmacokinetics of these analytes following the administration of a single dose of 140 mg. Methods: Positive electrospray ionisation (ESI) was used to detect catechin, epicatechin and procyanidin B1 on a Shimadzu-8040 mass spectrometer with (+)-catechin-2,3,4-13C3 as an internal standard. A double liquid-liquid extraction (LLE) method was used to extract the analytes from human plasma using 50 mM ammonium bicarbonate in water and ethyl acetate in the first extraction step and ethyl acetate: acetone (10:1, v/v) in the second. Chromatographic separation was achieved on an Agilent XDB-C8 column (4.6 x 100 mm, 5 µm) with a gradient method at a flow rate of 0.600 mL/min over a total run time of 10 minutes. The mobile phases consisted of water + 0.1% formic acid (A) and methanol + 0.1% formic acid (B). The analyte to internal standard peak area ratios were plotted against the nominal concentrations to generate a calibration curve with a quadratic regression weighted by 1/c2, over the range 19.5-2 500 ng/mL for catechin and epicatechin and 39.1-2 500 ng/mL for procyanidin B1. In an early phase clinical trial, sixteen healthy volunteers (four male and 12 female) were recruited. Eight participants received a placebo and the other eight were administered a dose of 140 mg of OxiprovinTM. Blood samples were collected at 0 hours (baseline) and at 1, 2, 3, 6 and 24 hours post administration of the supplement, and the resulting plasma was stored at -80°C until analysis. Results and Discussion: During inter-day validations, the average accuracy of calibration standards ranged from 93.5-106.3% (% CV 2.6-7.1%) for catechin, 96.7-103.1% (% CV 4.2-11.7%) for epicatechin and 90.0-103.5% (% CV 3.8-9.9%) for procyanidin B1. For quality controls, the average accuracy ranged from 97.7-106.8% (% CV = 6.9-14.7%), 93.1-101.6% (% CV = 4.9-14.7%) and 96.0-110.1% (% CV = 10.0-19.8%) for catechin, epicatechin and procyanidin B1, respectively. Endogenous matrix effects were shown to have negligible effects on the quantification of the analytes when plasma samples from six different sources were analysed. The average recovery of catechin, epicatechin and procyanidin B1 was 78.7%, 70.6% and 52.4%, respectively. Furthermore, catechin, epicatechin and procyanidin B1 were found to be stable in plasma when subjected to three freeze-thaw cycles, on bench at room temperature for up to six hours and at -80°C for 27 days. All three analytes were also found to be stable in whole blood for up to 2 hours on bench at room temperature. Lastly, 2% haemolysis did not affect the reproducibility of the method. The validated method was used to quantify catechin, epicatechin and procyanidin B1 in the human plasma samples obtained from the trial. During the trial, no adverse events were reported, and the supplement was well-tolerated. Upon analysis, no analytes were detected in the plasma samples obtained at each time point. Conclusion: A LC-MS/MS method was successfully developed and validated according to United Staes Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines for the quantification of catechin, epicatechin and procyanidin B1 in human plasma. The analytes were undetectable in the plasma samples collected at each time point during the trial. Due to impacts of metabolism, secondary metabolites may be detected at higher concentrations and using a more sensitive instrument may allow for lower assay ranges. Furthermore, future studies on urine or faecal samples may provide insight to the route of these parent compounds.
- ItemThe population pharmacokinetics of meropenem in adult patients with rifampicin-sensitive pulmonary tuberculosis(Frontiers Media S.A., 2021-06) Abulfathi, Ahmed A.; De Jager, Veronique; Van Brakel, Elana; Reuter, Helmuth; Gupte, Nikhil; Vanker, Naadira; Barnes, Grace L.; Nuermberger, Eric; Dorman, Susan E.; Diacon, Andreas H.; Dooley, Kelly E.; Svensson, Elin M.Background: Meropenem is being investigated for repurposing as an anti-tuberculosis drug. This study aimed to develop a meropenem population pharmacokinetics model in patients with pulmonary tuberculosis and identify covariates explaining inter-individual variability. Methods: Patients were randomized to one of four treatment groups: meropenem 2 g three times daily plus oral rifampicin 20 mg/kg once daily, meropenem 2 g three times daily, meropenem 1 g three times daily, and meropenem 3 g once daily. Meropenem was administered by intravenous infusion over 0.5-1 h. All patients also received oral amoxicillin/clavulanate together with each meropenem dose, and treatments continued daily for 14 days. Intensive plasma pharmacokinetics sampling over 8 h was conducted on the 14th day of the study. Nonlinear mixed-effects modeling was used for data analysis. The best model was chosen based on likelihood metrics, goodness-of-fit plots, and parsimony. Covariates were tested stepwise. Results: A total of 404 concentration measurements from 49 patients were included in the analysis. A two-compartment model parameterized with clearance (CL), inter-compartmental clearance (Q), and central (V1) and peripheral (V2) volumes of distribution fitted the data well. Typical values of CL, Q, V1, and V2 were 11.8 L/h, 3.26 L/h, 14.2 L, and 3.12 L, respectively. The relative standard errors of the parameter estimates ranged from 3.8 to 35.4%. The covariate relations included in the final model were creatinine clearance on CL and allometric scaling with body weight on all disposition parameters. An effect of age on CL as previously reported could not be identified. Conclusion: A two-compartment model described meropenem population pharmacokinetics in patients with pulmonary tuberculosis well. Covariates found to improve model fit were creatinine clearance and body weight but not rifampicin treatment. The final model will be used for an integrated pharmacokinetics/pharmacodynamics analysis linking meropenem exposure to early bactericidal activity.
- Item‘Building on shaky ground’—challenges to and solutions for primary care guideline implementation in four provinces in South Africa : a qualitative study(BMJ Publishing, 2020-05) Kredo, Tamara; Cooper, Sara; Abrams, Amber Louise; Muller, Jocelyn; Schmidt, Bey-Marrié; Volmink, Jimmy; Atkins, SallaObjectives Clinical guidelines support evidence-informed quality patient care. Our study explored perspectives of South African subnational health managers regarding barriers to and enablers for implementation for all available primary care guidelines. Design: We used qualitative research methods, including semistructured, individual interviews and an interpretative perspective. Thematic content analysis was used to develop data categories and themes. Setting: We conducted research in four of nine South African provinces with diverse geographic, economic and health system arrangements (Eastern Cape, Western Cape, KwaZulu-Natal, Limpopo). South Africa is a middle-income country with high levels of inequality. The settings represented public sector rural and peri-urban health facilities. Participants: Twenty-two participants with provincial and district health management roles, that comprised implementation and/or training on primary care guidelines, were included. Results: Participants recommended urgent consideration of health system challenges, particularly financial constraints, impacting on access to the guidelines themselves and to medical equipment and supplies necessary to adhere to guidelines. They suggested that overcoming service delivery gaps requires strengthening of leadership, clarification of roles and enhanced accountability. Participants suggested that inadequate numbers of skilled clinical staff hampered guideline use and, ultimately, patient care. Quality assurance of training programmes for clinicians—particularly nurses—interdisciplinary training, and strengthening post-training mentorship were recommended. Furthermore, fit-for-purpose guideline implementation necessitates considering the unique settings of facilities, including local culture and geography. This requires guideline development to include guideline end users. Conclusions: Guidelines are one of the policy tools to achieve evidence-informed, cost-effective and universal healthcare. But, if not effectively implemented, they have no impact. Subnational health managers in poorly resourced settings suggested that shortcomings in the health system, along with poor consultation with end users, affect implementation. Short-term improvements are possible through increasing access to and training on guidelines. However, health system strengthening and recognition of socio-cultural–geographic diversity are prerequisites for context-appropriate evidence-informed practice.
- ItemAn overview of analgesics - anticonvulsants, antidepressants, and other medications (Part 3)(AOSIS, 2019) Van Rensburg, R.; Reuter, H.ENGLISH ABSTRACT: Pain is classified by various descriptions. Chronic pain has been described as being neuropathic (due to nervous system lesions), nociceptive (due to tissue damage), or mixed (a combination of neuropathic and nociceptive). The addition of the term nociplastic pain is used to describe patients who experience chronic pain without tissue damage or nervous system lesions. Chronic pain is often difficult to manage, particularly neuropathic pain. Evidence-based pharmacological treatment options include anticonvulsants and antidepressants. The choice of medication will depend on various factors, including patient profile, type of pain, and associated conditions. Medications with the best evidence of efficacy for first-line use in neuropathic pain are the gabapentinoids, carbamazepine, the tricyclic antidepressants, and the serotonin-noradrenaline reuptake inhibitors duloxetine and venlafaxine. The cannabinoids and ketamine are being actively investigated for use in chronic pain. Currently the cannabinoids’ potential benefit is outweighed by the adverse effects, and recommendations for the use of ketamine is limited by its parenteral route of administration and low evidence of efficacy in chronic pain.
- ItemAn overview of analgesics : opioids, tramadol, and tapentadol (Part 2)(AOSIS, 2019) Van Rensburg, R.; Reuter, H.ENGLISH ABSTRACT: Pain can be caused by several mechanisms, and the development of chronic pain (also known as pain chronification) is a complex and often unpredictable process. Opioids, tramadol, and tapentadol provide pharmacological solutions to chronic pain of cancer or non-cancer origins, particularly if central sensitization is present. It may also be indicated for short-term use in acute pain. Despite large studies and meta-analyses of opioids for a variety of pain conditions, the evidence for its clinical effectiveness is still unclear. This is, however, mostly due to significant heterogeneity and bias between studies assessed. The dual analgesic mechanisms of tramadol and tapentadol appear to be effective options for pain relief, with an overall lower incidence of opioid-related adverse effects. Tapentadol has an analgesic effect comparable to the strong opioids, which appears to be mediated by its greater mu opioid receptor activity and more selective noradrenaline reuptake inhibition. Tramadol produces less analgesia than tapentadol, but it is also associated with reduced opioid-related adverse effects and dependence. The opioids and tramadol may be significantly affected by polymorphisms of CYP2D6, while this effect is lessened with tapentadol.