Effect of HIV infection on plasma exposure to first-line TB drugs and target attainment in children.

BACKGROUND: Whether HIV infection adversely affects exposure to first-line TB drugs in children is debatable. It is also not known whether HIV infection increases the risk of plasma underexposure or overexposure to TB drugs. This study sought to address these questions.DESIGN/METHODS: Children on TB treatment were enrolled. After 4 weeks on therapy, blood samples were collected at pre-dose, 1, 2, 4, 8, and 12 h post-dose for pharmacokinetic analysis. Plasma drug exposure below and above the lower and upper bounds of the 95% confidence intervals of the reference mean for children were considered underexposure and overexposure, respectively. The effect of HIV infection on drugs exposure and risk of underexposure were examined using multivariate analysis.RESULTS: Of 86 participants (median age: 4.9 years), 45 had HIV coinfection. HIV coinfection was associated with lower pyrazinamide (PZA) and ethambutol exposures in adjusted analysis. Patients with TB-HIV coinfection were three times more likely to have PZA underexposure than those with TB only. Underexposure of rifampin was common irrespective of HIV coinfection status.CONCLUSIONS: HIV coinfection was associated with a higher risk for PZA underexposure in children. This effect should be accounted for in models and simulations to determine optimal PZA dose for children.

Adequacy of WHO weight-band dosing and fixed-dose combinations for the treatment of TB in children.

BACKGROUND: We examined whether the updated WHO weight-band dosing recommendations and fixed-dose combination tablets for the treatment of TB in children achieves recommended calculated dosages and adequate drug plasma exposure.DESIGN/METHODS: Children on first-line TB treatment per WHO guidelines were enrolled. Blood sampling at pre-dose, 1, 2, 4, 8, and 12 h post-dose after at least 4 weeks of treatment was performed. Drugs concentrations were measured using validated liquid chromatography tandem with mass spectrometry and pharmacokinetic parameters calculated using noncompartmental analysis. Plasma drug exposure below the lower limit of the 95% confidence interval of the mean for children was considered low and above the upper limit was high.RESULTS: Of 71 participants, 34 (47.9%) had HIV coinfection. The median calculated dose for isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) was 10.0 (range 4.3-13.3), 15.0 (range 8.6-20.0), 30.0 (range 21.0-40.0), and 20.4 (range 14.3-26.7) mg/kg, respectively. Overall, most patients had under-exposure for RIF and PZA and over-exposure for INH and EMB. Drug dose and weight-for-age Z-score were associated with area under the curve from time 0-24 h for all drugs.CONCLUSIONS: Despite adherence to WHO dosing guidelines, low PZA and RIF plasma exposures were frequent in our study population. Higher than currently recommended dosages of RIF and PZA may be needed in children.

Antidiabetic activity of aqueous stem bark extract of Annickia polycarpa in alloxan-induced diabetic mice.

BACKGROUND AND AIM: There is a growing need to develop new drugs for type II diabetes mellitus (DM) from plant sources due to the high cost and adverse side effects of current drug therapies. To this end, the antidiabetic activity of aqueous stem-bark extract of A. polycarpa (APE) in alloxan-induced diabetic ICR mice was investigated. EXPERIMENTAL PROCEDURE: The effect of APE (20, 100 and 500 mg/kg), glibenclamide and metformin as positive controls, were determined over 4 weeks on fasting blood glucose (FBG). An oral glucose tolerance test (OGTT) was also conducted. The effects of these treatments on the morphology of the pancreas were assessed. In addition, phytochemical constituents and antioxidant properties of APE were determined. RESULTS AND CONCLUSION: APE, like glibenclamide and metformin, showed significant hypoglycaemic effect. The OGTT supported the hypoglycaemic effect. The destroyed pancreatic beta-cells in diabetic control mice were restored to normal by APE or drug treatment. APE showed antioxidant activity by scavenging DPPH free radicals; this may be due to the presence of phenolic compounds, particularly flavonoids. Thus, APE may act by restoring pancreatic beta-cell integrity through mopping of reactive oxygen species (ROS) associated with the diabetic state, and thereby improving pancreatic function and consequently, the lowering of FBG levels. These findings provide ample evidence to validate the traditional use of A. polycarpa in the management of DM.

Effect of malnutrition on the pharmacokinetics of anti-TB drugs in Ghanaian children.

BACKGROUND: Anti-TB drugs dosing based on weight alone may contribute to suboptimal drug concentrations and poor treatment outcomes in malnourished children. We examined the effect of malnutrition on the pharmacokinetics (PK) of first-line anti-TB drugs in children.METHODS: Drug concentrations were measured in Ghanaian children during the intensive phase of TB treatment. Weight-for-age (WFA), height-for-age (HFA), weight-for-height (WFH) and body mass index-for-age (BFA) were calculated and children with Z-scores < -2 SD (standard deviations) were considered as having malnutrition. PK differences of anti-TB drugs were compared by nutritional status.RESULTS: Of 100 participants, 24/48 (50.0%) of those younger than 5 years had wasting, 58/86 (67.4%) were underweight, and 56/99 (56.6%) had stunting; 22/51 (43.1%) children aged ≥5 years had low BFA. Children with stunting were more likely than controls to have lower mean peak concentration (Cmax) and area under the curve (AUC0-8h) of rifampin (RIF) and pyrazinamide (PZA), as well as a higher frequency of Cmax below the normal range. Wasting and underweight were associated with lower mean ethambutol (EMB) Cmax and AUC0-8h.CONCLUSIONS: The current WHO-recommended dosages were associated with lower plasma exposure of RIF, PZA and EMB in children with stunting, wasting and underweight. Anti-TB drugs dosing models for children may need to include height.

Safety and Effectiveness of Mist Antiaris, a Herbal Preparation for Treatment of Peripheral Neuropathy.

Mist Antiaris is a herbal decoction for treatment of nervous disorders. Safety and efficacy were evaluated in Sprague-Dawley rats and human patients, respectively. Acute toxicity was assessed by administration of a single 5000 mg/kg oral dose of decoction to a group of six rats. For subchronic toxicity, four groups of six rats each received water (control) or 10, 100, or 200 mg/kg oral doses of decoction daily for eight weeks. Body weight, serum, urine, and hematological profile of the animals in each group were monitored over the period. Effects of treatment on pentobarbital-induced sleeping time and histology of liver, lung, heart, and kidney tissue were assessed at the end of the study. There was no evidence of acute toxicity within 48 hours of the oral dose. Over the 8-week period, body weight increases in Mist Antiaris treatment groups were reduced relative to the control group. There were no significant differences in urine profile, serum biochemistry, hematological parameters, and pentobarbital-induced sleeping time. Tissue histology revealed no differences relative to controls. Assessment of efficacy was by retrospective review of data on patients who presented with peripheral neuropathy. Treatment resulted in 53.7 % of patients reporting complete resolution and 15.7 % showing reduction in neuropathic symptoms. The data demonstrate that there is no toxicity due to subchronic administration of Mist Antiaris in Sprague-Dawley rats. The reduction or resolution of neuropathic symptoms indicated by patents' file data provides evidence to suggest that Mist Antiaris has antineuropathic effects.

The Role of Nutritional Status on Follow-up among HIV-infected Children at a Teaching Hospital Clinic in Ghana.

BACKGROUND: Malnutrition and HIV infection in children interact adversely and may have a combined effect on clinical outcomes, including response to antiretroviral treatment (ART). Evidence of the role of malnutrition at the point of registration at HIV clinics is limited. This study sought to determine the role of nutritional status and other clinical factors on loss to follow-up (LTFU) among children at Komfo Anokye Teaching Hospital Pediatric HIV clinic in Kumasi, Ghana. STUDY DESIGN: A total of 324 HIV-positive children aged 1.5 to 10 years old who were registered at the clinic from January 1, 2007 to June 30, 2011 were included in this retrospective study. Weight-for-age z-score (WAZ) was used to classify nutritional status. Characteristics of children who were LTFU and those who remained in care were compared using bivariate analysis and logistic regression. RESULTS: At registration, 116 (35.8%) children were severely underweight (WAZ < -3) and 72 (22.2%) were underweight (WAZ < -2). A total of 163 (50.3%) children were LTFU during the course of one year. Malnourished children compared to normal weight children (WAZ > -2) were more likely to be LTFU (P = 0.003). Initiation of antiretroviral therapy was associated with a lower risk of LTFU. In the multivariate analysis, hospital admission (OR 4.38; 95% CI 2.30, 8.34) and initiation of ART (OR 0.33; CI 0.19, 0.56) were independently associated with LTFU. CONCLUSION: Malnutrition was common among Ghanaian HIV-infected children and appeared to be associated with a higher risk of hospitalization and LTFU. Irrespective of nutritional status, the initiation of ART was associated with better retention in care.

The unacknowledged impact of urinary schistosomiasis in children: 5 cases from Kumasi, Ghana.

Urinary schistosomiasis is a parasitic disease caused by Shistosoma haematobium. It is prevalent in several parts of Africa particularly in areas where there are large water bodies. In most affected communities, the condition is often accepted as normal since to them, all growing children pass blood in their urine and "grow out of it". Mass treatment of school children has been a regular exercise often undertaken by stake holders to decrease the disease burden and reduce transmission in selected communities. Urinary schistosomiasis can have devastating impact on the urinary tract which is often unacknowledged and unevaluated. Such omission could have implication for progressive renal damage which, if not detected and treated, could lead to end stage renal failure and death. We present five (5) cases of urinary schistosomiasis with severe obstructive uropathy seen at the paediatric nephrology/urology units of Komfo Anokye Teaching Hospital, Ghana. All five cases had some degree of anaemia and hypertension. Two of the five cases presented with end stage renal failure and died subsequently whilst two underwent successful surgery. One made a spontaneous recovery from the urinary obstruction though still has significant renal impairment. This potential devastating effect of urinary schistosomiasis on the kidneys calls for thorough evaluation and assessment of each confirmed case to include blood pressure measurement, full blood count, and ultrasonography of the urinary system. Mass screening programmes should be combined with portable ultrasonography of the kidneys, ureters and bladder.

Paediatric tuberculosis at the national teaching hospital CNHU-HKM of Cotonou, Benin: a retrospective study.

UNLABELLED: BACKGROIUND: Tuberculosis (TB) is a public health problem. Knowing its patterns could help address it more efficiently. OBJECTIVE: To determine the hospital incidence, presentation, management, and outcome of TB in our setting. METHODS: We conducted a chart review of children with TB during a five-year period at the University Hospital CNHU-HKM, Cotonou, Benin. RESULTS: Hospital prevalence of TB among hospitalised children was 0.2%. The mean age was six years, with a male:female ratio of 1.4:1. The common clinical features were: cough (78.1%), long standing fever (81.2%), growth retardation (65.6%), pulmonary consolidation (53.1%) and hepatosplenomegaly (34.4%). The skin tuberculin test was positive in only 40.6% of cases. Co-infection with HIV was present in 51.8% of cases. Mycobacterium tuberculosis could be identified in only 21.8% of cases. Twenty-six (81.2%) pulmonary tuberculosis (PTB) cases were diagnosed, eight (25%) of which were associated with extra pulmonary TB. Six (18.7%) presumed isolated extra PTB were also diagnosed. Eight-month treatment regimen was used in most patients, with mortality rate of 9.3%. CONCLUSION: Although TB hospital prevalence seems low in our setting, management needs to be improved according to guidelines.

d3-GHR genotype does not explain heterogeneity in GH responsiveness in hypopituitary adults.

OBJECTIVE: Heterogeneity in growth hormone (GH) responsiveness in adult hypopituitary patients receiving recombinant human GH (rhGH) is poorly understood; doses vary up to fourfold between individuals. Deletion of exon 3 in the GH receptor (d3-GHR) has been linked to enhanced rhGH responsiveness in children. We investigated the role of the d3-GHR polymorphism in determining adult rhGH responsiveness. METHODS: One hundred and ninety-four patients treated with an identical rhGH dosing protocol in a single centre were genotyped for the d3-GHR, and the results correlated with changes in serum IGF-I and clinical parameters of GH responsiveness after 6 and 12 months of GH replacement therapy. RESULTS: Allele frequencies for homozygous full length (fl/fl), heterozygous d3 (fl/d3) and homozygous d3 (d3/d3) were 52%, 38.7% and 9.3%, respectively, and were in Hardy-Weinberg equilibrium. Baseline IGF-I and DeltaIGF-I at 6 months were comparable between groups. DeltaIGF-I at 12 months was significantly greater in the d3/d3 group (P = 0.028). No difference was detected between fl/d3 and fl/fl groups. Regression analyses of DeltaIGF-I at 12 months and DeltaIGF-I/rhGH dose confirmed a significant relationship of d3/d3 genotype on rhGH response. There was no difference between groups in maintenance rhGH dose between genotypes. CONCLUSION: Homozygosity for d3-GHR confers a marginal increase in GH responsiveness at 12 months but without a detectable change in maintenance rhGH dose required. Both d3 alleles are required to achieve this response; given that only 10% of the population are d3 homozygotes, the d3GHR does not explain the marked heterogeneity of GH responsiveness in hypopituitary adults.

Malnutrition: missed opportunities for diagnosis.

INTRODUCTION: Malnutrition is a serious public health problem particularly in developing countries where it is responsible for 54% of under 5s mortality. Anthropometric measurements are key tools for the assessment of nutritional status and diagnosis of malnutrition. Height and weight measurements are not routinely done in most clinics and hospitals in Ghana. Children therefore miss the opportunity for accurate nutritional assessment and detection of malnutrition. OBJECTIVES: To determine the prevalence of wasting among children <5 years and to document extent of under-diagnosis. METHOD: From June to August 2004, children aged >3 months to <5 years attending the outpatient clinic of Komfo Anokye Teaching Hospital were systematically assessed for wasting using weight-for-height standard deviation score (Z-score). RESULTS: Of 1182 children (mean age 24.9 months), 251 (21.2%) were wasted, 48 (4.1%) of them severely. Only 15 (5.9%) of the 251 children with wasting were so identified by the attending physician. CONCLUSION: Malnutrition is widespread yet under-diagnosed. Anthropometric measurements should be promoted in all child health clinics.