Acute pharmacokinetics of first line anti-tuberculosis drugs in patients with Pulmonary Tuberculosis and in patients with Pulmonary Tuberculosis co-infected with HIV

The aim of this study was to compare the pharmacokinetics of antituberculosis drugs in patients with pulmonary tuberculosis (PTB) and in patients with PTB and HIV during the first 24 h of treatment. Designed as a case-control study, it compares the pharmacokinetics of first line antituberculous drugs, in HIV-positive (cases) and HIV-negative (control) patients both presenting with pulmonary tuberculosis. Blood samples were collected before and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 8, 12 and 24 h after administration of drugs. Drugs plasma levels were tested using HPLC assays. Results: Fourteen HIV positive (7 males and 7 females) and 17 HIV negative (9 males and 8 females) enrolled. Rifafour, a combination tablet including rifampicin, isoniazid, pyrazinamide and ethambutol was used in HIV positive patients, CD4 counts were significantly lower, renal function mildly decreased in 85% patients and moderately decreased in 7% patients. Liver function was normal in both groups. None of these patients was on other drug therapy. In the HIV positive group isoniazid T1/2 and AUC were decreased and Cl increased whereas Tmax and Cmax were unchanged. Pyrazinamide Tmax and Cmax were significantly decreased in HIV positive patients and no significant changes were noticed in the T1/2, AUC and CL. Conclusion: The study suggest that ethambutol, pyrazinamide and rifampicin pharmacokinetics was not affected by HIV infection and that isoniazid disposition is affected by HIV.Web of Scienc

Effect of diuretics on kidney stone-forming risk – an investigation using multiple timed urine collections

Introduction: Thiazide diuretics can lower urinary calcium excretion, helping to prevent recurrent calcium kidney stones. As dietary intake and urine chemistry varies throughout the day, a 24-h urine collection may not provide sufficient information to guide the optimal management in individual patients. Using multiple timed urine collections, we sought to identify times during the day when stone-forming risk is higher, allowing for therapy to be more accurately targeted. Methods: In a prospective study, healthy adult volunteers took a 4-week course of either hydrochlorothiazide (HCTZ) 25 mg/d or indapamide 2.5 mg/d. They were assessed at baseline, and at days 7, 14 and 28. At each time point, blood samples were taken for analysis and multiple timed urine samples were collected throughout the day, together with one overnight sample. Results: Diuretic treatment was well tolerated. Daily calcium and citrate excretion decreased, while ionized calcium and phosphate excretion were unchanged. Ionized calcium-divalent phosphate and ionized calcium-oxalate products were unchanged. In the timed urine samples, calcium excretion was decreased, particularly by indapamide, in the morning. Indapamide, but not HCTZ, decreased urinary citrate excretion, most obviously in overnight and early morning urines. No changes in ionized calcium were observed. Decreased divalent phosphate excretion was observed at several time points in the indapamide group. The ionized calcium-divalent phosphate product tended to decrease at most time points in both groups but no significant changes were observed in the ionized calcium-oxalate product. Conclusions: Indapamide 2.5 mg/d has a stronger protective effect against forming calcium kidney stones than HCTZ 25 mg/d. Most of the benefits appear to be achieved during the daytime and it may therefore be beneficial to prescribe medication twice daily or in the evening to maximize the protective effects of these agents. The benefits of indapamide treatment were attenuated by a reduction in urinary citrate excretion, an effect which has not been previously described

Investigation of the mechanism of fenfluramine-induced pulmonary phospholipidosis in the rat lung model

Magister Pharmaceuticae - MPharmThe aim of this study was to investigate the mechanism of fenfluramine-induced pulmonary phospholipidosis, by comparing the profile and levels of induced phospholipids in the rat and the mode of phospholipase inactivation, both relative to that produced by chlorphentermine. Wistar and BD9 rats were injected with fenfluramine (FF) and chlorphentermine (CP) intra-peritoneally daily over a six week period to induce phospholipidosis. The lungs isolated from such treated and untreated animals, were grouped into unlavaged lungs and lungs to be lavaged and from the latter group the alveolar macrophages were isolated. Small sections of the unlavaged lungs were microscopically examined to verify the induction of phospholipidosis. Further the levels of phosphatidyl choline (PC), spingomyelin (SPM), phosphatidyl ethanolamine (PE), phosphatidyl glycerol (PG), phosphatidyl inositol (PI), phosphatidyl serine (PS) and phosphatidic acid (PA) were determined in both groups of lungs using a TLC method. To assess whether the drug-mediated inactivation of the phospholipases (PL) occurred via direct inhibition of the enzymes or via the drug-phospholipid complex, the hydrolysis of the above phospholipids by PL-A or PL-C were monitored using colorimetric methods. The feasibility of the phospholipid-drug complex-mediated mechanism was further explored, by assessing the effect the two drugs had on the phase transition temperature of the phospholipids. Electron microscopy revealed the presence of hypertrophied and elevated counts of alveolar macrophages in the treated-Wistar and -BD9 rats. In the FF- and CP treated Wistar and BD9 rats there were, compared to the saline-treated rats, a 200 % and 235 % increase in macrophage counts, respectively, for the FF-treated rats and a 700 % and 965 % increase in macrophage counts, respectively, for the CP treated rats. The levels of all the phospholipids in the unlavaged lungs of both rat strains were elevated, except that for PG, PS and PA. In both rat strains following the treatment with both drugs the PG levels were not elevated and the PS levels were not elevated following CP treatment. Following the treatment for both drugs, the PA levels were also not elevated in the BD9 rats. Relative to the levels found in the unlavaged lungs of the control rats, the increases ranged from a minimum of 9 to a maximum of 216 %. In general, Wistar rats appeared to be more susceptible to both FF and CP treatment. In both rat strains, lavaging of the lungs considerably reduced the levels of phospholipids remaining in the lung and the differences between the treated and untreated animals became less striking. The addition of FF or CP, whether directly to the enzyme, or in the form of the drug phospholipid complex, resulted in significant decreases in the PL-A-mediated or PL-C-mediated hydrolysis of virtualy all the test phospholipids. The average decrease ranged from 0.811 to 4.04 ,.,.FFAbbb ,.,.1-1sample min-I, for the PL-A activity and 0.023 to 0.827 ,.,.gIp'CC100 ,.,.1-1 sample min-I, for the PL-C activity. In the case of FF, the inhibition of PL-A activity could not be ascribed exclusively to either direct inhibition of the enzyme or reduced susceptibility of the phospholipid substrate-drug complex. The PL-C activity appeared to be inhibited to a greater extent via the phospholipid substrate-drug complex rather than by direct inhibition. On the other hand, CP induced a small, but significantly greater degree of inhibition of PL-A activity, more via direct inhibition, rather than by the phospholipid substrate-drug complex. The PL-C activity appeared to be inhibited to a greater extent via phospholipid substrate-drug complexation than by direct inhibition. From the above data, considered collectively, it was not possible to declare either of the two possible mechanisms as the more likely one for FF or CP-induced inhibition of the phospholipases. The feasibility of the indirect mode was further explored, by determining the phase transition temperatures for the phospholipid-drug complexes of each drug. The addition of each drug caused a depression of the phase transition temperature of all the phospholipids with a .1T'dd ranging from 0.52 to 15.73 °C. This appears to support the notion that both drugs bind to the phospholipids and the differences in the extent of the phase transition temperature depression of the individual phospholipids may indicate differences in the binding capacities of these drugs. The following major conclusions may be drawn from the results of this investigation. Fenfluramine induces a phospholipidosis syndrome in the lungs of Wistar and BD9 rats that are histologically similar to that induced by CP. It induces the elevation of essentially the same phospholipids as CP, primarily in the alveolar spaces and macrophages, and by implication, most likely via similar mechanisms. For both FF and CP, both direct inhibition and phospholipid-drug complex-mediated inhibition of phospholipases were found to be a viable mechanism for this syndrome. The mechanism for FF-induced pulmonary phospholipidosis thus appears to be similar to that of CP; small quantitative differences in essentially similar mechanisms, may explain the differences in the levels of induced phospholipidosis found in this study

Bolus administration of intravenous glucose in the treatment of hyperkalemia : a randomized controlled trial

Please cite as follows:Chothia, M-Y. et al. 2014. Bolus Administration of Intravenous Glucose in the Treatment of Hyperkalemia: A Randomized Controlled Trial. Nephron Physiology, 1(26):1-8, doi:10.1159/000358836.The original publication is available at http://www.karger.com/Journal/Issue/261595Background: Hyperkalemia is a common medical emergency that may result in serious cardiac arrhythmias. Standard therapy with insulin plus glucose reliably lowers the serum potassium concentration ([K + ]) but carries the risk of hypoglycemia. This study examined whether an intravenous glucose- only bolus lowers serum [K + ] in stable, nondiabetic, hyperkalemic patients and compared this intervention with insulin-plus-glucose therapy. Methods: A randomized, crossover study was conducted in 10 chronic hemodialysis patients who were prone to hyperkalemia. Administration of 10 units of insulin with 100 ml of 50% glucose (50 g) was compared with the administration of 100 ml of 50% glucose only. Serum [K + ] was measured up to 60 min. Patients were monitored for hypoglycemia and EKG changes. Results: Baseline serum [K + ] was 6.01 ± 0.87 and 6.23 ± 1.20 mmol/l in the insulin and glucose-only groups, respectively (p = 0.45). At 60 min, the glucose-only group had a fall in [K + ] of 0.50 ± 0.31 mmol/l (p < 0.001). In the insulin group, there was a fall of 0.83 ± 0.53 mmol/l at 60 min (p < 0.001) and a lower serum [K + ] at that time compared to the glucose-only group (5.18 ± 0.76 vs. 5.73 ± 1.12 mmol/l, respectively; p = 0.01). In the glucose-only group, the glucose area under the curve (AUC) was greater and the insulin AUC was smaller. Two patients in the insulin group developed hypoglycemia. Conclusion: Infusion of a glucose-only bolus caused a clinically significant decrease in serum [K + ] without any episodes of hypoglycemia.Post-prin

HbA1c of 6.5% to diagnose diabetes mellitus – Does it work for us? – The Bellville South Africa study

Diabetes is a disease fuelled by the increasing worldwide obesity epidemic with significant morbidity and mortality, and the World Health Organization (WHO) estimates that it will affect 366 million individuals worldwide by 2030 [1]. Its diagnosis was previously made either according to the WHO criteria which were updated in 2006 [2] using a fasting blood glucose sample and subsequent 75 g oral glucose tolerance test (OGTT) with blood taken for glucose determination again 2 hours after an oral glucose challenge, or according to the American Diabetes Association (ADA) criteria which were updated in 2005 [3], using only a fasting blood glucose level. Using ADA criteria only has been found to underestimate the prevalence of diabetes and misses those individuals with impaired glucose tolerance (IGT), a pre-diabetic state [4]. The disadvantage of both these diagnostic approaches is that they require the patient to fast and if need confirming, would require a second fasting sample. Glucose also has a large biological and diurnal variation and depends on recent carbohydrate intake and the OGTT is fairly invasive [5]. In 2010, the ADA updated their diagnostic criteria to include an OGTT as well [6]. On the other hand, HbA1c, which is formed by the attachment of glucose to various amino groups of haemoglobin and has been used since 1977 for the long-term (2–3 month) glycaemic control follow up of diabetes, has recently been advocated by the ADA as a diagnostic tool. In 2009, the International Expert Committee of the ADA issued a statement proposing an HbA1c value of 6.5% (48 mmol/mol) as a diagnostic level for the diagnosis of diabetes. This value was chosen, as it was found to be the value after which the incidence of retinopathy, a common complication that often is present before the actual diagnosis of diabetes is made, is increased [7]. This test would be advantageous, as it does not require a fasting sample and has much less intraindividual variation.University Research Fund of the Cape Peninsula University of Technology, South Africa and the National Health Laboratory Services South Africa (grant number 94122

Deterioration, improvement of kidney function over time and determinants in the Cape Town Bellville South cohort

Aim: The aim of the present study was to assess the trajectories of glomerular filtration rate (GFR) and determinants of change during a 3-year period in free-living mixed-ancestry South Africans. Methods: In all 320 (78.1% women) adults, aged 56.2 years, from Cape Town were examined in 2008 and 2011. Estimated glomerular filtration rate (eGFR) was based on the Modification of Diet in Renal Disease model; and staging of eGFR used the National Kidney Foundation’s classification. Results: Mean eGFR (mL/min per 1.73 m2 ) was 68.6 at baseline and eGFR stages were: >90 (9.4%), 60–90 (58.7%), 30–60 (28.1%) and <30 (0.9%). eGFR increased by 8 mL/min during follow-up, reflecting variable trajectories by baseline eGFR stages, sex, hypertension and glucose tolerance (all P-interaction ≤0.012). Movements across eGFR stages during follow-up favoured improvement in 113 participants (35.3%), and worsened in 23 (7.2%). In adjusted multinomial logistic regressions, men had a 72% (43– 86%) lower chance of improvement, while each mmHg higher systolic blood pressure conferred a 7% (3–11%) risk of deterioration. Equivalent for each 1% HbA1c was 30% (8–56%). Participants with glucose intolerance had 102% (3–297%) higher chances of improvement than diabetics. Conclusion: Variable trajectories of eGFR with time were observed in this cohort, reflecting the effects of modifiable risk factors such as hypertension and dysglycaemia.This research was supported by a grant from the University Research Fund of the Cape Peninsula University of Technology, South Africa

Exploring the notion of knowing, doing and being in the Teaching

Exploring the notion of knowing, doing and being in the Teaching Development Programme (TDP) through the frame of activity theory Research in Innovation, Teaching and Learning Conference – RITAL 2012, Cape Town, 11 December 201

Negative association of MC3R variants with weight and blood pressure in Cape Town pupils aged 11–16 years

Background. Human and animal studies support the role of MC4R and MC3R in human obesity, but limited data are available on the genetic contribution to obesity in South African populations. Objective. To screen obese-overweight South African pupils for MC3R and MC4R polymorphisms that may play a role in the development of obesity. Design. A cross-sectional study screened 227 obese-overweight (115 black and 112 coloured) and 204 normal weight (94 black, 110 coloured) school pupils for the presence of MC4R and MC3R polymorphisms using a single strand conformation polymorphism, subsequent sequencing, and allele specific restriction enzyme analysis. Results. Two polymorphisms were detected in the MC3R (T6K and V81I) but none in MC4R. After adjusting for age, gender and case-control status, the frequency distributions of T6K and V81I genotype and allele varied significantly between the ethnic groups. The frequency of the V81I A allele was significantly lower in coloured overweight-obesity than normal pupils. In coloured pupils, both polymorphisms were associated with obesity indices and total cholesterol. The T6K A allele was also associated with lower blood pressure. Likewise, different T6K-V81I haplotypes demonstrated negative associations with obesity indices and blood pressure. Conclusion. We demonstrated that the MC3R polymorphisms have a protective effect on metabolic traits; however, further analysis is required to confirm whether this translates to a lower incidence of metabolic syndrome in coloured populations.University Research Fund of the Cape Peninsula University of Technology, Harry Crossley and the National Health Laboratory Services

Two-phase simulations as a development tool for thixoforming processes

The aim of this study was to investigate whether blood cell membrane monounsaturated fatty acids were associated with inflammation and disease outcome in patients with multiple sclerosis. The fatty acid composition in peripheral blood mononuclear cell and red blood cell membranes from 26 patients and 25 controls were determined by gas chromatography. Results showed positive associations between C-reactive protein and C16:1n-7, C18:1n-7, and C24:1n-9 in membranes from controls only. In general, C18:1n-9 and C20:1n-9 showed inverse correlations, while C16:1n-7 and C18:1n-7 showed positive correlations with disease outcome. Multiple sclerosis has a known inflammatory component. There is scarcity of literature on the role of monounsaturated fatty acids in inflammation, but results from this study suggested an association in healthy subjects between monounsaturated fatty acids and C-reactive protein, even at physiologically low levels. This association was not found in the plasma from patients. Furthermore, the n-9 and n-7 fatty acids played different roles in disease outcome, and therefore warrant inclusion, together with polyunsaturated fatty acids when investigating the inflammatory aspects of the disease.This study was funded by grants from the University Research Fund of the Cape Peninsula University of Technology, South Africa