Clinical Pharmacology

Permanent URI for this community

https://scholar.sun.ac.za/handle/10019.1/164

This division was known as Pharmacology until 27 June 2013.

Browse

Now showing 1 - 20 of 127

The 12-month period prevalence and cardiac manifestations of HIV in patients with acute coronary syndrome at a tertiary hospital in Cape Town, South Africa : a retrospective cross-sectional study
(BMC (part of Springer Nature), 2021) Pennefather, Camilla; Esterhuizen, Tonya; Doubell, Anton; Decloedt, Eric H.
Background: HIV-positive patients are increasingly being affected by non-communicable diseases such as coronary artery disease (CAD). Data from high-income countries (HICs) indicate that HIV-positive patients have different riskfactor profiles for acute coronary syndrome (ACS) as well as different cardiac manifestations of this syndrome compared to HIV-negative patients. There is limited data from Sub-Saharan Africa (SSA), and particularly from South Africa with the biggest HIV epidemic in the world. The objective of this study was to determine the 12-month period prevalence of HIV in patients with ACS and to compare the risk-factor profile, ACS presentation and management between HIV-positive and HIV-negative adults. Methods: We included all patients hospitalised with ACS from 01 January to 31 December 2018 in a tertiary hospital, Tygerberg Hospital, in Cape Town, South Africa. The HIV-status of all patients was determined using routine clinical records. We performed multiple conditional logistic regression on HIV-positive and HIV-negative patients (1:3 ratio) to compare the risk factor profile, ACS presentation and management between the groups. Results: Among 889 patients, 30 (3.4%) were HIV-positive (95% confidence interval (CI): 2.3–4.8). HIV-positive patients were younger, more frequently men, and had a lower prevalence of medical comorbidities and a family history of CAD. They were more likely to present with ST-elevation myocardial infarction (STEMI) [odd’s ratio (OR) (95% CI): 3.12 (1.2–8.4)], and have single-vessel disease [OR (95% CI): 3.03 (1.2–8.0)]. Angiographic and echocardiographic data, as well as management, did not differ between the groups. Among HIV-positive patients, 17 (65%) were virally suppressed (HIV viral load < 200 copies/mL) with a median CD4+ count of 271 cells/mm3. The majority (20, 67%) of HIV-positive patients were receiving antiretroviral therapy at the time of the ACS. Conclusions: We found an HIV-prevalence of 3.4% (95% CI 2.3–4.8) in adults with ACS in a high endemic HIV region. HIV-positive patients were younger and more likely to present with STEMIs and single-vessel disease, but had fewer CAD risk factors, suggesting additional mechanisms for the development of ACS.
A 3-year survey of acute poisoning exposures in infants reported in telephone calls made to the Tygerberg Poison Information Centre, South Africa
(Health & Medical Publishing Group, 2016-03) Marks, Carine J.; Van Hoving, D. J.
ENGLISH ABSTRACT: Background. Infants undergo rapid development changes and are particularly vulnerable to toxic chemicals. Identifying and evaluating the toxic risks that exist in this age group could be very valuable when making recommendations on how to prevent specific types of poisoning. Objectives. This study analysed the toxic substances responsible for acute poisoning exposures in infants (<1 year of age) as well as the severity of the exposures. Methods. A retrospective analysis of the Tygerberg Poison Information Centre (TPIC) database was conducted over a 3-year period (1 January 2011 to 31 December 2013). Descriptive statistics are provided for the entire study population as well as for the neonatal subgroup (<30 days old). Results. The TPIC handled 17 434 consultations during the 3-year study period. Infants were involved in 1 101 cases (6.3%), of which 46 cases (4.2%) were neonates. Most enquiries about infants were associated with non-drug chemicals (n=824, 74.8%). Pharmaceuticals were involved in 185 cases (16.8%) followed by biological exposures (e.g. snake and spider bites, scorpion stings, plant and mushroom poisonings) (n=109, 9.9%). Most infants (n=987, 89.6%) presented with no or only minor symptoms. In neonates, 17 (37.0%) presented with moderate to severe toxicity. Six of these (35.3%) were poisoned by complementary and alternative medicines. Conclusion. Most poisoning exposures in infants are not serious and can be safely managed at home after contacting a poison centre. Identification and documentation of poisoning in this special population is of great importance.
Aberrant apoptotic response of colorectal cancer cells to novel nucleoside analogues
(Public Library of Science, 2015) Harmse, Leonie; Dahan-Farkas, Nurit; Panayides, Jenny-Lee; Van Otterlo, Willem; Penny, Clement
Despite the increased understanding of colorectal cancer and the introduction of targeted drug therapy, the metastatic phase of the disease remains refractory to treatment. Since the deregulation of normal apoptosis contributes to the pathogenesis of colorectal cancer, novel nucleoside analogues were synthesized here and evaluated for their ability to induce apoptosis and cause cell death in two colorectal adeno-carcinoma cell lines, Caco-2 and HT-29. Three novel nucleoside analogues assessed here showed cytotoxic activity, as measured by the MTT assay against both cell lines: the IC50 values ranged between 3 and 37 μM, with Caco-2 cells being more sensitive than HT-29 cells. Compared to camptothecin, the positive control, the nucleoside analogues were significantly less toxic to normal unstimulated leukocytes (p>0.05). Moreover, the nucleosides were able to induce apoptosis as measured by an increase in caspase 8 and caspase 3 activity above that of the control. This was additionally supported by data derived from Annexin V-FITC assays. Despite marginal changes to the mitochondrial membrane potential, all three nucleosides caused a significant increase in cytosolic cytochrome c (p>0.05), with a corresponding decrease in mitochondrial cytochrome c. Morphological analysis of both cell lines showed the rapid appearance of vacuoles following exposure to two of the nucleosides, while a third caused cellular detachment, delayed cytoplasmic vacuolisation and nuclear abnormalities. Preliminary investigations, using the autophagic indicator monodansylcadaverine and chloroquine as positive control, showed that two of the nucleosides induced the formation of autophagic vacuoles. In summary, the novel nucleoside analogues showed selective cytotoxicity towards both cancer cell lines and are effective initiators of an unusual apoptotic response, demonstrating their potential to serve as structural scaffolds for more potent analogues.
Abnormal serum lipoprotein levels as a risk factor for the development of human lenticular opacities
(Clinics Cardiv Publishing, 2003-04) Meyer, D.; Parkin, D.; Maritz, F. J.; Liebenberg, P. H.
Aim: To determine whether an association exists between the different plasma lipoprotein constituents and the prevalence of lenticular opacities in dyslipidaemic subjects. Methods: Adult patients (n = 115) of both genders were included if their fasting total serum cholesterol concentrations exceeded the 95th percentile of normal or their serum low-density lipoprotein (LDL) : high-density lipoprotein (HDL) ratios exceeded 5. Patients were excluded if they suffered from any condition known to cause, or predispose them to, elevated lipoprotein levels or lenticular opacification. Lenticular changes were assessed by means of a slit-lamp through the fully dilated pupil. Results: An extremely strong association (p < 0.0001) was found to exist between HDL cholesterol levels and the development of lens opacities. Below an HDL-C level of 1.5 mmol/l subjects had a seven-fold higher calculated probability of falling in the lens opacity subgroup than those with HDL-C levels above 1.5 mmol/l [odds ratio = 7.33 (95% CI = 2.06–26.10; p = 0.001)]. An equally strong association was found between high (>5) LDL:HDL ratios and the development of lens opacities (p < 0.0003). The risk of falling into the cataract subgroup if the individual’s LDL:HDL ratio exceeded 5 was 2.35 (95% CI = 1.09–5.04; p = 0.014). Conclusions: This study strongly suggests that an association exists between low levels of HDL cholesterol and high LDL:HDL ratios on one hand and the development of adult lens opacification on the other.
Accelerating clinical evaluation of repurposed combination therapies for COVID-19
(American Society of Tropical Medicine and Hygiene, 2020-08-21) Rayner, Craig R.; Dron, Louis; Park, Jay J. H.; Decloedt, Eric H.; Cotton, Mark F.; Niranjan, Vis; Smith, Patrick F.; Dodds, Michael G.; Brown, Fran; Reis, Gilmar; Wesche, David; Mills, Edward J.
As the global COVID-19 pandemic continues, unabated and clinical trials demonstrate limited effective pharmaceutical interventions, there is a pressing need to accelerate treatment evaluations. Among options for accelerated development is the evaluation of drug combinations in the absence of prior monotherapy data. This approach is appealing for a number of reasons. First, combining two or more drugs with related or complementary therapeutic effects permits a multipronged approach addressing the variable pathways of the disease. Second, if an individual component of a combination offers a therapeutic effect, then in the absence of antagonism, a trial of combination therapy should still detect individual efficacy. Third, this strategy is time saving. Rather than taking a stepwise approach to evaluating monotherapies, this strategy begins with testing all relevant therapeutic options. Finally, given the severity of the current pandemic and the absence of treatment options, the likelihood of detecting a treatment effect with combination therapy maintains scientific enthusiasm for evaluating repurposed treatments. Antiviral combination selection can be facilitated by insights regarding SARS-CoV-2 pathophysiology and cell cycle dynamics, supported by infectious disease and clinical pharmacology expert advice. We describe a clinical evaluation strategy using adaptive combination platform trials to rapidly test combination therapies to treat COVID-19.
Accuracy Optimization of anti-TB Drug Assays using Protein Evaluation in Calibration Curves during Pharmacokinetics Quality Assurance
(Stellenbosch : Stellenbosch University, 2021-12) Vallie, Sarfaraaz; Stander, Marietjie; Reuter, Helmuth; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. Medicine: Clinical Pharmacology.
ENGLISH ABSTRACT: Quality assurance of drug assaying is an important aspect in clinical testing. Accuracy is important to ensure correct bio-analytical results by constructing calibration curves that took blood matrix interferences into consideration. I have adhered to the United States of America Food and Drug Administration (FDA) call for improved accuracy in bio-equivalence, bio-availability and administering of narrow therapeutic indexed drugs. Significant different plasma levels were observed in clinical trials for the occasional hyperproteinemia (an increase in protein concentration in the bloodstream) and hypoproteinemia (lower-than normal levels of protein in the blood) patients this includes disease-related hyperalbuminemia (an increased concentration of albumin in the blood) and hypoalbuminemia (a deficit of albumin in the blood) patients. This research supported a modeled approach for accuracy improvements by including the patients‘ plasma protein levels using a combined calibration curve (protein evaluation calibrations curves – PROTECC-PKTM). Levels of albumin were classified as marked hypoalbuminemia (<2.5 g/dL), mild hypoalbuminemia (2.5-3.5 g/dL), normal albumin (3.5-4.5 g/dL), and hyperalbuminemia (>4.5 g/dL). This research was specifically important for drugs with a narrow therapeutic index. The rifampicin method was developed, validated and the concentration calibration curve of rifampicin with and without plasma was assessed. The limit of detection for rifampicin with and without plasma was 0.189 μg/ml ± 0.082 and 0.080 μg/ml ± 0.053 μg/ml respectively (LOD ± mean standard diviation). The limit of quantification of rifampicin with and without plasma was 0.573 μg/ml ± 0.082μg/ml and 0.243 μg/ml ± 0.053μg/ml respectively (LOQ ± mean standard diviation). The r2 for rifampicin was 0.9971 without plasma and 0.9852 with plasma present. A novel analytical method for determination of the % protein content present in blood plasma was performed using the Karl Fischer Titration process. Results indicated deviation in % protein of blood plasma for patients compared to literature values of about 8 %. Using the data obtained, the PROTECC-PKTM curves indicated that the relative accuracy differed by a minimum of 0.1% for low binding affinity drugs and a maximum of more than 20% for drugs with moderate binding affinities. The relative accuracy of the anti TB drugs was supported by computational modelling and thermodynamic analytical methods for each drug during multiple drug co-administration regimens. This study focused on the drug binding affinity that affects the extrapolation of the patient‘s sample drug concentration from the slope of LCMS calibration curve. The binding constants calculated from fluorescence spectroscopy data were as follows: rifampicin 5.379 x 102 M-1 (moderate affinity), isoniazid 9.285 M-1 (low affinity), 25-desacetyl rifampicin 3.156 M-1 (low affinity), ethambutol 3.443 M-1 (low affinity) and pyrazinamide 3.076 X 102 M-1 (moderate affinity). These drugs Gibbs free energies for these drugs indicated spontaneous binding reactions. Rifampicin, a non-polar weak acid with a higher affinity, showed the most stable complex formation with human serum albumin (HSA) compared to soluble isoniazid. This is because isoniazid in its ionized form can be easily excreted in the urine resulting in low levels of detection. This will affect the bioavailability and accuracy of the assay levels for patients experiencing hyper and hypoalbuminemia with related competition and induction processes of the enzymes. These complications are apparent where a larger number of patients are involved in clinical trials, bioequivalence and bioavailability studies with varying protein levels that may be more crucial for drugs with a narrow therapeutic index.
Acute poisonings : a comparative study of hospital admissions versus poison centre consultations
(Stellenbosch : Stellenbosch University, 2001-12) Marks, C. J.; Muller, G. J.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine. Division of Pharmacology.
ENGLISH ABSTRACT: A prospective study was conducted in 1999 to establish the incidence and nature of acute poisonings in the Cape Town / Western Cape region. This study was based on an analysis of Poison Centre queries and acute poisoning admissions to Tygerberg Hospital over a period of 1 year (1999). Summary of findings for Hospital admissions (1010 cases): Acute poisonings were more common in adults (83%) than in children (17%) and drug overdose was by far the most common clinical entity in adult Hospital admissions (89% of cases). Most overdoses in adults were intentional (97%). Seventy five percent of these cases were female, predominantly in the 20-40 year age group. The incidence of non-drug chemical exposures in adults was relatively low (11%). In children, on the other hand, there was much less of a discrepancy between drug and non-drug chemical exposures (41% and 59% respectively). Paracetamol was the drug most commonly used in overdose in both adults and children. In adults ethanol featured in 17% of cases. Ingestion of paraffin and related volatile hydrocarbons were the most important cause of acute poisoning in children. Acute poisoning admissions due to drugs of abuse, excluding ethanol, were minimal in both age groups (1%). Toxic exposures to non-drug chemicals in the agricultural and industrial settings were low (3%). The number of exposures to biological toxins was also minimal (2%). Summary of findings for Poison Centre inqueries (3744 consultations): In 1999 the Tygerberg Poison Information Centre received 3744 calls, of which 2690 were related to acute human exposures to poisonous substances. The remainder of the calls (1054) was either about drug therapy, or general non-patient related toxicological matters. There were more calls regarding poisoning in adults (61%) than in children (39%). Most of the paediatric poisonings were accidental (97%), whereas in adults 55% were deliberate and 45% accidental. Forty four percent of the children and 52% of adults were female. In children, inqueries about exposures to potentially harmful non-drug household chemical products comprised 56% of poison calls, while drug overdose was 28% and exposures to biological toxins 16%. In adults 44% of inqueries were with regard to household products, 40% about drugs and 16% biological toxins. A comparison of Hospital admissions versus Poison Centre consultations: In order to make a valid comparison between Hospital admissions and Poison Centre consultations, acute poisoning cases originating from the same area were compared. Eight hundred and thirty four (90%) of patients admitted to Tygerberg Hospital and 592 (25%) of Poison Centre consultations originated from the same region, the Tygerberg catchment area. Several differences were noted when comparing poisoning cases reported to the Poison Centre and Hospital admissions. Six hundred and eighty eight (83%) adults and 145 (17%) children were admitted to Hospital in contrast to Poison Centre inqueries, where 322 (54%) were adults and 270 (46%) children. In adults, 99% of Hospital admissions versus 59% of Poison Centre consultations were regarded as self-inflicted. Ninety three percent of adults admitted to Hospital were drug overdoses, whereas only 48% of adult Poison Centre consultations involved ingestion of medicines. In adult overdoses with paracetamol and other analgesics, tricyclic antidepressants, antiepileptics, theophylline and ethanol were significantly higher in Hospital admissions than in Poison Centre consultations. In contrast, exposures to pesticides e.g. pyrethroids, misuse of recreational drugs e.g. cannabis and biological toxin exposures e.g. spider bites, were significantly higher in Poison Centre consultations than in Hospital admissions. In children, poisoning exposures to volatile hydrocarbons, especially paraffin, were significantly higher in Hospital admissions compared to Poison Centre enqueries. As is evident from the disparity in the results above, inqueries to the Tygerberg Poison Information Centre cannot be regarded as a reflection of the true incidence of acute poisonings in the community. Poison Information Centre statistics are distorted because of two factors: 1. Under-reporting to the Poison Information Centre. Healthcare providers are familiar with how to manage drugs commonly used in overdose (e.g. paracetamol) and certain household non-drug chemicals (e.g. paraffin), and often do not consult the Poison Centre for poison cases involving these substances. The number of inqueries received by the Poison Information Centre regarding these substances is, therefore, an under representation of actual incidence. 2. Over-reporting to the Poison Information Centre. The Tygerberg Poison Information Centre is well known for its expertise in biological toxins (e.g. spider and snake bites, scorpion stings, plant and mushroom ingestions, and marine toxins). Therefore, the number of inqueries received by the Centre with regard to these exposures is far higher than actual incidence of exposures. It is clear from this study that one cannot use data derived from a poison centre alone as an indicator of true incidence of poisoning in the community. A more accurate estimate of incidence of acute poisoning could be obtained by including data from hospital admissions, as well as those from primary health care facilities. Another prominent finding in this study was the high incidence of self-inflicted drug overdose in adult females, with paracetamol being the drug of choice. Poison prevention should therefore not be limited to children. Adult prevention programs need urgent attention.
Adverse drug reactions in paediatric in-patients in a South African tertiary hospital
(Stellenbosch : Stellenbosch University, 2017-12) Makiwane, Memela MacDonald; Decloedt, Eric; Rosenkranz, Bernd; Kruger, Mariana; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine: Clinical Pharmacology.
ENGLISH SUMMARY: Purpose: Paediatric patients have more adverse drug reaction (ADR) rates than adults due to off-label use of medicines and the prevalence data of ADRs in Sub-Saharan African children is limited. The aim was to describe the prevalence and nature of ADRs in paediatric (≤ 16 years old) in-patients at a tertiary hospital in South Africa. Methods: We conducted a prospective study of paediatric in-patients to identify suspected ADRs. Children had to be admitted for at least 24 hours during the 3-month study period (1 December 2015 to 29 February 2016). The data collected included age, sex, diagnosis and medicines received. We assessed causality using the 10-question Naranjo probability scale and classified severity using the Hartwig severity scale. Results: We found that 18.4% (52/282) of patients had 61 ADRs. The median age of patients with ADRs was 1.4 years (interquartile range (IQR): 0.5 – 5.3 years). ADR was the reason for admission in a third of the patients (31%; 16/52). Paediatric oncology patients suffered the majority of the ADRs (56.5%; 13/23), followed by HIV-infected patients on antiretroviral therapy (ART) (42.9%; 9/21) and tuberculosis (TB) patients (17.5%; 7/40). HIV-TB coinfected patients also experienced a high 30.8% (4/13) rate of ADRs. The majority of the ADRs were moderate 45.9% (28/61), while 42.6% (26/61) were mild, and 11.5% severe ADRs (7/61). These ADRs range from severe neutropaenia 4.9% (3/61) and drug induced liver injury (DILI) 4.9% (3/61) to mild cutaneous rashes 13.1% (8/61). There were no fatal ADRs, while 13.1% (8/61) ADRs were considered life threatening; 27.9% (17/61) necessitated and/or prolonged hospitalisation and 31.1% (19/61) resulted in persistent or significant disability or incapacity. Thirty eight percent of ADRs (23/61) were predictable. Paediatric oncology patients on chemotherapy were 7 times more likely to have ADR(s) than other patient groups [OR 7.3 (3.0 – 17.9), p < 0.01]. More ADRs were associated with chemotherapy 44.3% (27/61) and antimicrobials 42.6% (26/61), while the other miscellaneous medicine classes were associated with 34.4% (21/61) of the recorded ADRs. Conclusion: The prevalence of ADRs was 18.4% and in 31% the ADR was the reason for admission. The ADRs in paediatric oncology patients were expected, but of note nearly half the HIV-infected patients (43%) suffered an ADR.
Aminoglycoside monitoring: Perspective on current trends in the Western Cape
(Health and Medical Publishing Group (HMPG), 2005) Van der Bijl, P.
[No abstract available]
An analytical investigation of the impact of crushing of first-line antituberculosis medication and administration via a nasogastric tube
(Stellenbosch : Stellenbosch University, 2022-11) Phogole, Cassius; Kellermann, Tracy; Faculty of Medicine and Health Sciences. Dept. of Medicine. Division of Clinical Pharmacology.
ENGLISH ABSTRACT: Background Currently, the treatment of TB patients admitted to an intensive care unit (ICU) in South African Hospitals is performed by the off-label practice of crushing the first-line antituberculosis drugs isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA) and ethambutol (EMB) and administration to the patients through a nasogastric (NG) tube as the majority of these patients are often sedated or intubated and therefore cannot swallow the whole tablets. This has, however, been associated with low drug exposure insufficient to effectively treat the Mycobacterial infection. Additionally, there is a paucity of alternative intravenous (IV) formulations of first-line antituberculosis drugs, especially in developing countries. The stability and solubility of these crushed drugs dissolved in water are questionable. Furthermore, the impact of the removal of the protective outer tablet coating and its effect on absorption and subsequent bioavailability has not been elucidated in the literature. Moreover, drug loss of crushed first-line antituberculosis drugs by adsorption to the surface materials used during medication preparation and administration via NG tube has also not been documented. Therefore, the present study aimed to investigate the root cause of the poor plasma drug exposure observed when crushing the first-line antituberculosis drugs and administration through an NG tube using laboratory-based techniques with possible translational interventions that can be applied in clinical settings to ameliorate their bioavailability. Methods The aqueous solubility of crushed drugs under the inversion mixing method was evaluated against easily implementable mixing methods (sonication and vortexing) with/without ascorbic acid (Asc). Moreover, the aqueous stability assessment of these crushed first-line antituberculosis drugs in mono-suspensions with/without Asc and co-suspensions at room and low temperatures was executed as well. The stability of the whole/crushed tablets in fasted-state simulated gastrointestinal fluids (FSSGIFs) was evaluated with/without Asc. Lastly, the drug loss by adsorption to the surface materials used during medication preparation and in vitro administration through an NG tube was quantitatively determined. Results Rifampicin (RIF) was the only drug showing poor aqueous solubility and instability in the simulated-gastric fluid. However, the addition of Asc has been shown to significantly (P<0.001) improve RIF solubility in both water and FSSGIFs with no detrimental effects. A minimum recommended volume of water (10 ml) to rinse the NG tube after administration of medication was shown to be inadequate to clear off all the residues of crushed antituberculosis medication. However, when an additional rinsing step with another 10 mL of water (total volume of 20 mL) was employed in the current study the amount of APIs of crushed first-line antituberculosis drugs adsorbed to these surface materials was significantly (p<0.001) reduced. Conclusion Co-administration of first-line antituberculosis medication with Asc when off-label crushing practice is used may improve RIF bioavailability. Furthermore, rinsing the NG tube with 20 mL of water after administering TB medication was shown to ensure adequate drug delivery, which may improve the bioavailability of nonpolar drugs that adhere to the surface of an NG tube.
Angio-oedema associated with colistin
(Health & Medical Publishing Group, 2016) Abulfathi, A. A.; Greyling, T.; Makiwane, M.; Esser, M.; Decloedt, E.
ENGLISH ABSTRACT: A 50-year-old woman known to have type 1 diabetes mellitus presented with a rare case of angio-oedema associated with colistin use. The angio-oedema was temporally associated with the use and discontinuation of colistin with the reasonable exclusion of important differential diagnoses. Pseudoallergy may be a probable underlying mechanism. However, we cannot exclude the possibility of hereditary angio-oedema type 2 or 3, or that her concomitant medications (particularly enalapril) and her renal impairment contributed to the risk and severity of her angio-oedema.
Another look at erythromycin
(Health & Medical Publishing Group, 1978-04) Straughan, J. L.
ENGLISH ABSTRACT: The erythromycins are broadly reviewed from a clinical viewpoint. The antimicrobial spectrum, clinical indications, pharmacokinetics and toxicity are dealt with. The usefulness of erythromycin for respiratory tract infections is stressed. New evidence to support bactericidal activity of this antibiotic is noted. There seems little reason to use the potentially hepatotoxic estolate form of erythromycin. The safety of the other forms of this antibiotic available in this country is emphasized.
Antimycobacterial agents : a study of Liposomal-Encapsulation, comparitive permeability of bronchial tissue and in vitro activity against mycobacterium tuberculosis isolates
(Stellenbosch : Stellenbosch University, 2012-12) Van Rensburg, Lyne; Van Zyl, J. M.; Seifart, H. I.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine. Pharmacology.
ENGLISH ABSTRACT: In this thesis, research results are reported on the role of dipalmitoyl phosphatidyl choline (DPPC) and DPPC-liposomes on the in vitro permeability characteristics of various antimycobacterial drugs across porcine bronchial tissue. The permeability flux values of the different compounds (isoniazid, ofloxacin and moxifloxacin) and their relevant DPPC formulations were determined using a continuous flow through perfusion system. Mean steady state flux values were compared statistically by means of a t-test at a significance level of 5% as well as an F-test using whole curve comparisons. The results indicated that the different formulations of drug and their DPPC combinations retard the permeation of drug through bronchial tissue. However, moxifloxacin permeation was significantly enhanced when in a DPPC-liposomal formulation. These results demonstrate the important role that molecular weight, electrostatic charge, partitioning of the molecules in DPPC and DPPC-liposomes play in transmembrane diffusion. In addition, the effect of individual drugs and their DPPC combinations on the surface tension lowering property of DPPC was evaluated. The results obtained showed minimal decreases in the surface tension lowering capability of DPPC; however, the minimal increases in surface tension do not alter the integrity of DPPC to a large extent. Drug susceptibility testing of Mycobacterium tuberculosis cultures against the individual antitubercular drugs and their DPPC combinations was done by using the Radiometric BACTEC 460TB™ system. Drug-entrapped DPPC liposomes were tested at concentrations comparable to their relative minimum inhibitory concentrations (MIC). The results for the BACTEC assay indicated that the mycobacteria were susceptible to the developed drug entrapped liposomes; of which their encapsulation efficiencies for the relevant drugs were approximately ± 50%. It was concluded that drug-entrapped DPPC liposomes could fulfill the dual role of pulmonary drug delivery and alveolar stabilization due to antiatelectatic effect of DPPC which can improve the distribution of anti-tubercular drugs in the lung
Application of Caco-2 cell line in herb-drug interaction studies : current approaches and challenges
(Canadian Society for Pharmaceutical Sciences, 2014-01) Awortwe, C.; Fasinu, P. S.; Rosenkranz, B.
The Caco-2 model is employed in pre-clinical investigations to predict the likely gastrointestinal permeability of drugs because it expresses cytochrome P450 enzymes, transporters, microvilli and enterocytes of identical characteristics to the human small intestine. The FDA recommends this model as integral component of the Biopharmaceutics Classification System (BCS). Most dedicated laboratories use the Caco-2 cell line to screen new chemical entities through prediction of its solubility, bioavailability and the possibility of drug-drug or herb-drug interactions in the gut lumen. However, challenges in the inherent characteristics of Caco-2 cell and inter-laboratory protocol variations have resulted to generation of irreproducible data. These limitations affect the extrapolation of data from pre-clinical research to clinical studies involving drug-drug and herb-drug interactions. This review addresses some of these caveats and enumerates the plausible current and future approaches to reduce the anomalies associated with Caco-2 cell line investigations focusing on its application in herb-drug interactions.
Artemisia Spp. derivatives for COVID-19 treatment : anecdotal use, political hype, treatment potential, challenges, and road map to randomized clinical trials
(American Society of Tropical Medicine and Hygiene, 2020) Kapepula, Paulin M.; Kabengele, Jimmy K.; Kingombe, Micheline; Van Bambeke, Francoise; Tulkens, Paul M.; Kishabongo, Antoine Sadiki; Decloedt, Eric; Zumla, Adam; Tiberi, Simon; Suleman, Fatima; Tshilolo, Leon; Muyembe-TamFum, Jean-Jacques; Zumla, Alimuddin; Nachega, Jean B.
The world is currently facing a novel COVID-19 pandemic caused by SARS-CoV-2 that, as of July 12, 2020, has caused a reported 12,322,395 cases and 556,335 deaths. To date, only two treatments, remdesivir and dexamethasone, have demonstrated clinical efficacy through randomized controlled trials (RCTs) in seriously ill patients. The search for new or repurposed drugs for treatment of COVID-19 continues. We have witnessed anecdotal use of herbal medicines, including Artemisia spp. extracts, in low-income countries, and exaggerated claims of their efficacies that are not evidence based, with subsequent political controversy. These events highlight the urgent need for further research on herbal compounds to evaluate efficacy through RCTs, and, when efficacious compounds are identified, to establish the active ingredients, develop formulations and dosing, and define pharmacokinetics, toxicology, and safety to enable drug development. Derivatives from the herb Artemisia annua have been used as traditional medicine over centuries for the treatment of fevers, malaria, and respiratory tract infections. We review the bioactive compounds, pharmacological and immunological effects, and traditional uses for Artemisia spp. derivatives, and discuss the challenges and controversies surrounding current efforts and the scientific road map to advance them to prevent or treat COVID-19.
Association between health-related quality of life and medication adherence in pulmonary tuberculosis in South Africa
(Frontiers Media, 2017-12-18) Kastien-Hilka, Tanja; Rosenkranz, Bernd; Schwenkglenks, Matthias; Bennett, Bryan M.; Sinanovic, Edina
Background: Health-related quality of life (HRQOL) and adherence to treatment are two often inter-related concepts that have implications for patient management and care. Tuberculosis (TB) and its treatment present a major public health concern in South Africa. The study aimed to evaluate the association between HRQOL and adherence in TB patients in South Africa. Methods: Four self-reported HRQOL and one self-reported adherence measures were used in an observational longitudinal multicentre study during 6-month standard TB treatment. These included the generic Short-Form 12 items (SF-12) and European Quality of Life 5 dimensions 5 levels (EQ-5D-5L), the disease-specific St. George's Respiratory Questionnaire (SGRQ) and the condition-specific Hospital Anxiety and Depression Scale (HADS) for HRQOL. Adherence was measured by the Morisky Medication Adherence Scale 8 items (MMAS-8). The relationship between both concepts was examined in 131 patients using Spearman's rho correlations, and linear regression models. Results: HRQOL improved over 6-month TB treatment, whereas adherence mean scores stayed constant with participants attaining a medium average level. Around 76% of patients reported to be high adherers and 24% were reporting a medium or low adherence. Associations between HRQOL and adherence were mainly weak. High adherence at treatment start was positively related to improvements in anxiety and depression after 6-month treatment. The overall improvement in pain and discomfort, and psychosocial health aspects over treatment time was positively, but weakly associated with adherence at 6 months of treatment. Conclusion: A positive relationship exists between adherence and HRQOL in TB in a South African setting, but this relationship was very weak, most likely because HRQOL is affected by a number of different factors and not limited to effects of adherence. Therefore, management of TB patients should, besides adequate drug treatment, address the specific mental and psychosocial needs.
B-cell and T-cell activation in South African HIV-1-positive non-Hodgkin’s lymphoma patients
(Medpharm Publications, 2018) Flepisi, Brian T.; Bouic, Patrick; Sissolak, Gerhard; Rosenkranz, Bernd
Background: Altered immune mechanisms play a critical role in the pathogenesis of non-Hodgkin’s lymphoma (NHL). HIV-1 (HIV) infection is associated with a state of excessive T-cell activation, which can lead to increased T-cell turnover and lymph node fibrosis. Objectives: This study aimed to determine the serum levels of circulating B-cell activation markers, and the expression of T-cell activation and regulatory markers in HIV-positive NHL patients. Method: The serum levels of circulating soluble(s) sCD20, sCD23, sCD27, sCD30 and sCD44 molecules, all of which are biomarkers of B-cell activation, were determined by enzyme-linked immunosorbent assays (ELISA), while biomarkers of T-cell activation (CD8+CD38+) and regulation (FoxP3) were determined by flow cytometry in 141 subjects who were divided into five groups: Combination antiretroviral therapy (ART)-naïve HIV-positive patients; ART-treated HIV-positive patients; HIV-negative NHL patients; HIV-positive NHL patients on ART; and healthy controls. Results: HIV-positive NHL patients had significantly higher serum levels of sCD20, sCD23, sCD30 and sCD44 than HIV-negative NHL patients, while all five biomarkers were significantly elevated in HIV-positive NHL patients when compared with ART-treated HIV-positive patients. HIV-positive NHL patients had higher CD8+CD38+ and lower FoxP3 expression than HIV-negative NHL and ART-treated HIV-positive patients. Conclusion: B-cell activation is increased in HIV-positive NHL patients and is associated with reduced regulatory T-cell populations and increased CD8+ T-cell activation.
Berg adder (Bitis atropos) : an unusual case of acute poisoning
(Health and Medical Publishing Group, 2017) Wium, C. A.; Marks, C. J.; Du Plessis, C. E.; Muller, G. J.
A 5-year-old boy presented to hospital with mild local cytotoxic and severe neurotoxic symptoms. The neurotoxic symptoms included ptosis, fixed dilated pupils and flaccid paralysis with respiratory failure. Mild hyponatraemia was also a clinical feature. After various unsuccessful treatment options were followed, the Tygerberg Poison Information Centre was contacted and a diagnosis of berg adder bite was made. Berg adder bites are uncommon and therefore not usually considered in the differential diagnosis of a patient presenting with an unexplained clinical picture. A timeous poison information helpline consultation is recommended in this situation.
Biomarkers of HIV associated malignancies and of drug interaction between anti-retrovirals (ARVs) and chemotherapy
(Stellenbosch : Stellenbosch University, 2015-12) Flepisi, Thabile Brian; Rosenkranz, Bernd; Bouic, Patrick J. D.; Sissolak, Gerhard; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine: Clinical Pharmacology.
ENGLISH ABSTRACT: INTRODUCTION: Altered immune mechanisms play a critical role in the pathogenesis of Non-Hodgkin lymphoma (NHL), as evidenced by increased rates of NHL among HIV+ patients [De Roos et al., 2012; Mellgren et al., 2012]. AIMS: To determine whether biomarkers of B-, T-cell activation, and inflammation are elevated in HIV+NHL patients; and whether cART influences their expression. METHODS: The expression of CD8+CD38 and FoxP3 were determined by flow cytometry; the serum concentrations of circulating sCD20, sCD23, sCD27, sCD30 and sCD44 were determined by enzyme linked immunosorbent assay (ELISA); and the serum concentrations of circulating IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, and TNF-α were determined by meso-scale discovery (MSD) assay in 141 participants consisting of HIV positive NHL (HIV+NHL), HIV negative NHL (NHL); combination antiretroviral treated HIV+ (HIV+ cART), treatment naive HIV+ (cART-naïve HIV+) patients; and healthy controls. RESULTS: HIV+NHL patients had higher serum concentrations of sCD20 (p<0.0001 and p=0.0359), sCD23 (p=0.0192 and p<0.0001), sCD30 (p=0.0052 and p<0.0001), sCD44 (p=0.0014 and p<0.0001), and IL-4 (p=0.0234 and p=0.03360); and lower expression of FoxP3 (p<0.0001 and p=0.0171) as compared to NHL and HIV+ cART patients. As compared to NHL patients, the serum concentrations of IL-2 (p=0.0115), and TNF-α (p=0.0258) were higher in HIV+NHL patients, while those of IL-1β (p=0.0039) were significantly lower. HIV+NHL patients had higher expression of CD8+CD38 (p=0.0104), serum concentrations of IFN-γ (p=0.0085), and IL-6 (p=0.0265); and lower serum concentrations of IL-12p70 (p=0.0012) than HIV+ cART patients. As compared to controls, NHL had higher concentrationsof all biomarkers investigated except FoxP3 expression. As compared to HIV+ cART and controls, cART-naïve HIV+ patients had higher concentrations of all biomarkers investigated except sCD23 and FoxP3 expression. CONCLUSION: Biomarkers of chronic B- and T-cell activation and inflammation are up-regulated in HIV+NHL and the untreated HIV+ state. cART decreases immune activation and inflammation.
Biomarkers of HIV-associated cancer
(Libertas Academica, 2014) Flepisi, Brian Thabile; Bouic, Patrick; Sissolak, Gerhard; Rosenkranz, Bernd
Cancer biomarkers have provided great opportunities for improving the management of cancer patients by enhancing the efficiency of early detection, diagnosis, and efficacy of treatment. Every cell type has a unique molecular signature, referred to as biomarkers, which are identifiable characteristics such as levels or activities of a myriad of genes, proteins, or other molecular features. Biomarkers can facilitate the molecular definition of cancer, provide information about the course of cancer, and predict response to chemotherapy. They offer the hope of early detection as well as tracking disease progression and recurrence. Current progress in the characterization of molecular genetics of HIV-associated cancers may form the basis for improved patient stratification and future targeted or individualized therapies. Biomarker use for cancer staging and personalization of therapy at the time of diagnosis could improve patient care. This review focuses on the relevance of biomarkers in the most common HIV-associated malignancies, namely, Kaposi sarcoma, non-Hodgkin’s lymphoma, and invasive cervical cancer.

Browse

Browsing Clinical Pharmacology by Title

Results Per Page

Sort Options