Browsing by Subject "Drugs"

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    Open Access
    A description of the pharmacokinetics of first line anti-tuberculosis drugs and adjunctive corticosteroid therapy in the pericardial compartment and their effect on cytokine profiles in the pericardial compartment of patients with tuberculous pericarditis
    (2025) Shenje, Justin Tapiwa; Ross, Ian
    Tuberculous pericarditis is caused by Mycobacterium tuberculosis infection of the pericardium, which is associated with a higher mortality, compared with pulmonary tuberculosis. Constrictive pericarditis, a significant complication of tuberculous pericarditis, contributes to this elevated mortality. Adjunctive corticosteroid therapy with prednisolone, has been shown to reduce the incidence of constrictive pericarditis by more than 50%. However, this is associated with significant side effects, especially in patients with HIV co-infection. Constrictive pericarditis is only partially responsible for this increased mortality, whereas other factors including delayed diagnosis of tuberculosis, cardiac complications for example, pericardial tamponade and poor pericardial exposure of anti-TB drugs also likely contribute. The pharmacokinetics of anti-tuberculous (TB) drugs within the pericardial space remain poorly understood and until now have relied on studies of pulmonary tuberculosis. While adjunctive corticosteroids have been shown to be beneficial, there are no available data on the pharmacokinetics of prednisolone in the pericardium, and uncertainty remains as to whether an empiric dose of 120 mg prednisolone is the optimal dose for reducing the incidence of constrictive pericarditis or whether it is detectable at the site of infection, to exert its pharmacodynamic effect. Combining anti-TB treatment and high doses of prednisolone are likely to have a profound effect on the immune response, therapeutic effect and cortisol milieu in the pericardium. I was therefore interested in investigating the impact of this therapeutic combination, through direct sampling of the pericardial fluid in patients with tuberculous pericarditis. Methods: A total of 16 patients with newly diagnosed tuberculous pericarditis and a pericardial effusion requiring pericardial aspiration, were enrolled into the study. The patients were randomly assigned to 120 mg of prednisolone or matching placebo and were simultaneously started on first line World Health Organization (WHO) anti-tuberculosis treatment, namely, rifampicin, isoniazid, ethambutol and pyrazinamide. Intensive pharmacokinetic samples were collected at the following timepoints, just before administration of the anti-tuberculosis treatment and prednisolone or placebo and at 0.5 hour, 1 hour, 2 hour, 3 hour, 5 hour, 8 hour and 24 hour intervals thereafter for the first 24 hours. Intensive pharmacokinetic samples were collected from plasma, pericardial fluid and saliva. The pharmacokinetics of rifampicin, isoniazid, ethambutol and pyrazinamide in the pericardium were described so as to assess the adequacy of conventional doses of the WHO first line anti-TB treatment regimen. The study also described the pharmacokinetics of 120 mg of prednisolone and evaluated its effect on endogenous corticosteroids and cytokines. Furthermore, the study compared the immunological response to tuberculous pericarditis in plasma and pericardium. Results: While pericardial drug exposures to isoniazid and pyrazinamide were comparable to those of plasma, there was a reduction in rifampicin and ethambutol exposure in the pericardium, which were 20%; (p<0.0010) and 55%; (p<0.0010) of their respective plasma drug exposures. The median pericardial rifampicin concentration was 0.125 mg/L, which was lower than the reference minimum inhibitory concentration (MIC) for Mycobacterium tuberculosis isolates, which was 0.208 mg/L (p=0.0010). The pharmacokinetic profile of prednisolone in the pericardium was similar to that of the plasma, but there was a 1.60 hours delay (p=0.0320) in time to maximum concentration (Tmax) in the pericardial space. Adjunctive corticosteroid therapy administered as a single dose of 120 mg of prednisolone, was associated with 83% reduction in median plasma interleukin-6 (p=0.0360), a 50% reduction in median plasma interleukin-8 (p=0.0300) and a 50% reduction in median pericardial interleukin-8 (p=0.0400). Prior to administration of glucocorticoids, the pericardial cortisol/ cortisone ratio was twice that of plasma (p=0.0050). A similar elevation of the cortisol/ cortisone ratio at the site of infection has previously been described in the bronchial lavage fluid of patients with pulmonary tuberculosis. Among those participants who did not receive glucocorticoids, pericardial cytokine interferon-gama, tumour necrosis-alpha, interleukin-6, interleukin-8, interleukin-10, and interferon gamma-induced protein-10 concentration increases were multiples fold higher than their corresponding plasma concentrations, (p=0.0011), (p=0.0043), (p=0.0009), (p=0.0001), (p=0.0054) and (p=0.0031), respectively. Conclusion: By directly sampling the pericardial fluid among patients with tuberculous pericarditis, I was able to gain novel insights, which have never previously been described. The reduced pericardial rifampicin and ethambutol exposures, below the required minimum inhibitory concentrations in the pericardial space, are of great concern, particularly, considering the relative importance of rifampicin in the treatment of drug sensitive tuberculosis. This warrants a revision of the dosing strategy, or a review of therapeutic regimen used in tuberculous pericarditis, to enhance efficacy. Prednisolone administered at a dose of 120 mg daily orally is detectable with high exposure in the pericardium and may explain the beneficial effect observed in tuberculous pericarditis among HIV negative individuals, through its alteration in the cytokine milieu, and lower propensity to developing constrictive pericarditis. Additionally, the raised cortisol/ cortisone ratio at the site of infection, the pericardium, compared with other matrices especially plasma may indicate an immunomodulatory role either to dampen an excessive or evoke an immunological response.
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    Open Access
    Access to diagnostic tests and essential medicines for cardiovascular diseases and diabetes care: cost, availability and affordability in the west region of Cameroon
    (Public Library of Science, 2014) Jingi, Ahmadou M; Noubiap, Jean Jacques N; Onana, Arnold Ewane; Nansseu, Jobert Richie N; Wang, Binhuan; Kingue, Samuel; Kengne, André Pascal
    Objective: To assess the availability and affordability of medicines and routine tests for cardiovascular disease (CVD) and diabetes in the West region of Cameroon, a low-income setting. METHODS: A survey was conducted on the availability and cost of twelve routine tests and twenty medicines for CVD and diabetes in eight health districts (four urban and four rural) covering over 60% of the population of the region (1.8 million). We analyzed the percentage of tests and medicines available, the median price against the international reference price (median price ratio) for the medicines, and affordability in terms of the number of days' wages it would cost the lowest-paid unskilled government worker for initial investigation tests and procurement for one month of treatment. RESULTS: The availability of tests varied between 10% for the ECG to 100% for the fasting blood sugar. The average cost for the initial investigation using the minimum tests cost 29.76 days' wages. The availability of medicines varied from 36.4% to 59.1% in urban and from 9.1% to 50% in rural settings. Only metformin and benzathine-benzylpenicilline had a median price ratio of ≤1.5, with statins being largely unaffordable (at least 30.51 days' wages). One month of combination treatment for coronary heart disease costs at least 40.87 days' wages. CONCLUSION: The investigation and management of patients with medium-to-high cardiovascular risk remains largely unavailable and unaffordable in this setting. An effective non-communicable disease program should lay emphasis on primary prevention, and improve affordable access to essential medicines in public outlets.
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    Development of 3D multicellular liver organoids derived from human induced pluripotent stem cells to model antiretroviral therapy induced liver injury
    (2025) Maepa, Setjie Welcome; Ndlovu, Hlumani
    Introduction: The liver is an essential organ in the body responsible for the synthesis of serum proteins, biotransformation, and detoxification of xenobiotic drugs. Drug cytotoxicity studies have been conducted using cancer-derived cell lines which are inferior. In the present study, we developed and demonstrated the use of robust and tractable 3D multicellular human liver organoids (HLOs) to model drug induced liver injury (DILI) by exposing HLOs to Antiretroviral therapy drugs (ART), combination of ART and antituberculosis drugs (A+TB) and Schistosoma mansoni egg soluble antigen (SEA) or Troglitazone (TGZ). Methods: A quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR) was adopted to confirm stage specific gene marker and we validated the presence of multiple cell lineages using flow cytometry. Enzyme-linked immunosorbent assay (ELISA) was employed to determine cytokine levels in ART/SEA/TGZ treated HLOs. A mass spectrometry-based proteomics approach was applied to decipher protein dynamics and molecular mechanisms of ART, A+TB and TGZ -induced liver injury in treated HLOs. Results: HLOs exhibited robust mature hepatic gene markers (CYP3A4, ATA1, ALB and HNF4-α), reduction in pluripotency (OCT-4, Nanog, and Sox2) and the definitive endoderm (SOX17 and GSC) markers. Flow cytometry using EpCAM, CD166 and CD68 antibodies indicated that HLOs comprise of 60,4% EpCAM+ cells, 11,2% EpCAM-/CD166+ cells and 5% EpCAM-/CD68+ cells, respectively. HLOs exhibited high CYP3A4 enzyme activity compared to HepaRG 3D model. Proinflammatory (IL-6, IL-1β and TNF-α) and anti-inflammatory (IL-4 and IL-10) cytokines were elevated in both models. IL-4 was more pronounced in SEA-treated HLOs only. Proteomic analysis successfully showed differentially expressed proteins (DEPs) in ART-HLOs, A+TB-HLOs (TGZ-HLOs compared controls. Functional enrichment of these DEPs in ART-HLO, A+TB-HLO and TGZ groups based on Gene ontology (GO), and KEGG pathway showed these proteins were associated with immunity and inflammation, oxidative stress, protein synthesis, neutrophil extracellular traps (NETs) formation, the ATP-dependent chromatin remodelling and necroptosis. Conclusion: We successfully generated multicellular 3D liver organoids consisting of hepatocytes, Kupffer cells and hepatic stellate cells. Proteomic data revealed that ART, A+TB and TGZ alters the expression of proteins mostly involved immunity and inflammation and mitochondrial functions, augmented oxidative stress, and necroptosis.
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    Hazardous and Harmful use of Alcohol and / or Other Drugs and Health Status Among South African Patients Attending HIV Clinics
    (Springer, 2013) Kader, R; Seedat, S; Govender, R; Koch, J R; Parry, C D
    There is growing recognition of the influence of substance use, particularly alcohol use, on HIV disease progression. This study investigated how hazardous/harmful use of alcohol and drugs impacts the health status of 1503 patients attending HIV clinics. Of the sample, 37 % indicated hazardous/harmful drinking and 13 % indicated a drug problem. Hazardous/harmful use of alcohol and drugs was significantly related to health status, with participants using substances more likely to have TB-positive status (χ2 = 4.30, p < 0.05), less likely to be on ARVs (χ2 = 9.87, p < 0.05) and having lower CD4 counts (t = 4.01, p < 0.05). Structural equation modelling confirmed the centrality of hazardous/harmful use of alcohol as a direct and indirect determinant of disease progression. Based on these findings it is recommended that patients attending HIV clinics be routinely screened for problematic alcohol and/or drug use, with strong emphasis on ensuring ARV adherence in those with problematic alcohol use.
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    Negative attributions towards people with substance use disorders in South Africa: Variation across substances and by gender
    (Biomed Central Ltd, 2012) Sorsdahl, Katherine; Stein, Dan; Myers, Bronwyn
    BACKGROUND:Little research has examined attitudes towards people who use substances in low and middle income countries (LMIC). Therefore, the present study examined the attributions made by the general South African population about people who use substances and whether these attributions differ by the type of substance being used, the gender of the person using the substance, or the characteristics of the person making the attribution.METHOD:A convenience sample of 868 members of the general public was obtained through street-intercept methods. One of 8 vignettes portraying alcohol, cannabis, methamphetamine or heroin, with either a male or female as the protagonist was presented to each respondent. Respondents' attitudes towards the specific cases were investigated. RESULTS: Respondents held equally negative views of the presented substances, with the exception of the cannabis vignette which was considered significantly less "dangerous" than the alcohol vignette. Respondents were more likely to offer "help" to women who use alcohol, but more likely to suggest "coercion into treatment" for men. Individuals who scored higher on the ASSIST were more likely to hold negative attitudes towards substance users and black African respondents were more likely to offer help to individuals who use substances. CONCLUSION: The stigma associated with substance use in South Africa is high and not necessarily dependent on the drug of choice. However, a range of factors, including gender of the substance user, and ethnicity of the rater, may impact on stigma. Interventions designed to strengthen mental health literacy and gender-focused anti-stigma campaigns may have the potential to increase treatment seeking behaviour.