Research Articles (Clinical Pharmacology)
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- 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.
- ItemAn overview of analgesics : NSAIDs, paracetamol, and topical analgesics Part 1(Taylor and Francis, 2019) Van Rensburg, R.; Reuter, H.ENGLISH ABSTRACT: Pain is a complex and unique experience. It encompasses several pathways, involving nociceptive signal generation (transduction) and propagation (transmission), as well as perception and modulation of the nociceptive stimuli. Nonsteroidal anti-inflammatory drugs (NSAIDs) primarily exert their analgesic effects through inhibition of cyclooxygenase (COX) enzymes, thereby attenuating prostaglandin synthesis. The COX-2 selective NSAIDs (coxibs) and aspirin have also been shown to reduce colorectal cancers, presumably by prostaglandin-inhibition mechanisms. Paracetamol appears to have both peripheral and central effects. The postulated mechanism for its peripheral effects is indirect COX inhibition, while the central effects are thought to be mediated by modulation of descending pain inhibition pathways. Topical analgesics are available in various formulations. The topical NSAIDs have the same mechanism of action as the systemic formulations, but with less systemic absorption and effects. The local anaesthetics provide a dense sensory block via inhibition of nerve impulse transmission, and are available in percutaneous and transdermal preparations. Capsicum is effective for neuropathic pain, and acts by stimulating and then desensitising peripheral sensory nerves.