A phase I trial to evaluate the safety and pharmacokinetics of low-dose methotrexate as an anti-malarial drug in Kenyan adult healthy volunteers

<p>Abstract</p> <p>Background</p> <p>Previous investigations indicate that methotrexate, an old anticancer drug, could be used at low doses to treat malaria. A phase I evaluation was conducted to assess the safety and pharmacokinetic profile of this drug in healthy adult male Kenyan volunteers.</p> <p>Methods</p> <p>Twenty five healthy adult volunteers were recruited and admitted to receive a 5 mg dose of methotrexate/day/5 days. Pharmacokinetics blood sampling was carried out at 2, 4, 6, 12 and 24 hours following each dose. Nausea, vomiting, oral ulcers and other adverse events were solicited during follow up of 42 days.</p> <p>Results</p> <p>The mean age of participants was 23.9 ± 3.3 years. Adherence to protocol was 100%. No grade 3 solicited adverse events were observed. However, one case of transiently elevated liver enzymes, and one serious adverse event (not related to the product) were reported. The maximum concentration (C_max) was 160-200 nM and after 6 hours, the effective concentration (C_eff) was <150 nM.</p> <p>Conclusion</p> <p>Low-dose methotraxate had an acceptable safety profile. However, methotrexate blood levels did not reach the desirable C_effof 250-400-nM required to clear malaria infection <it>in vivo</it>. Further dose finding and safety studies are necessary to confirm suitability of this drug as an anti-malarial agent.</p

Guidelines for Field Surveys of the Quality of Medicines: A Proposal

Paul Newton and colleagues propose guidelines for conducting and reporting field surveys of the quality of medicines

The content of African diets is adequate to achieve optimal efficacy with fixed-dose artemether-lumefantrine: a review of the evidence

A fixed-dose combination of artemether-lumefantrine (AL, Coartem®) has shown high efficacy, good tolerability and cost-effectiveness in adults and children with uncomplicated malaria caused by Plasmodium falciparum. Lumefantrine bioavailability is enhanced by food, particularly fat

Global proteomic analysis of plasma from mice infected with Plasmodium berghei ANKA using two dimensional gel electrophoresis and matrix assisted laser desorption ionization-time of flight mass spectrometry.

Malaria-infection in mice results in a wide perturbation of the host serum proteome involving a range of proteins and functions. Of particular interest is the increased secretion of anti-inflammatory and anti apoptotic proteins

Partial HIV C2V3 envelope sequence analysis reveals association of coreceptor tropism, envelope glycosylation and viral genotypic variability among Kenyan patients on HAART

Background: HIV-1 is highly variable genetically and at protein level, a property it uses to subvert antiviral immunity and treatment. The aim of this study was to assess if HIV subtype differences were associated with variations in glycosylation patterns and co-receptor tropism among HAART patients experiencing different virologic treatment outcomes. Methods: A total of 118 HIV env C2V3 sequence isolates generated previously from 59 Kenyan patients receiving highly active antiretroviral therapy (HAART) were examined for tropism and glycosylation patterns. For analysis of Potential N-linked glycosylation sites (PNGs), amino acid sequences generated by the NCBI’s Translate tool were applied to the HIVAlign and the N-glycosite tool within the Los Alamos Database. Viral tropism was assessed using Geno2Pheno (G2P), WebPSSM and Phenoseq platforms as well as using Raymond’s and Esbjörnsson’s rules. Chi square test was used to determine independent variables association and ANOVA applied on scale variables. Results: At respective False Positive Rate (FPR) cut-offs of 5% (p = 0.045), 10% (p = 0.016) and 20% (p = 0.005) for CXCR4 usage within the Geno2Pheno platform, HIV-1 subtype and viral tropism were significantly associated in a chi square test. Raymond’s rule (p = 0.024) and WebPSSM (p = 0.05), but not Phenoseq or Esbjörnsson showed significant associations between subtype and tropism. Relative to other platforms used, Raymond’s and Esbjörnsson’s rules showed higher proportions of X4 variants, while WebPSSM resulted in lower proportions of X4 variants across subtypes. The mean glycosylation density differed significantly between subtypes at positions, N277 (p = 0.034), N296 (p = 0.036), N302 (p = 0.034) and N366 (p = 0.004), with HIV-1D most heavily glycosylated of the subtypes. R5 isolates had fewer PNGs than X4 isolates, but these differences were not significant except at position N262 (p = 0.040). Cell-associated isolates from virologic treatment success subjects were more glycosylated than cell-free isolates from virologic treatment failures both for the NXT (p = 0.016), and for all the patterns (p = 0.011). Conclusion: These data reveal significant associations of HIV-1 subtype diversity, viral co-receptor tropism, viral suppression and envelope glycosylation. These associations have important implications for designing therapy and vaccines against HIV. Heavy glycosylation and preference for CXCR4 usage of HIV-1D may explain rapid disease progression in patients infected with these strains

The content of African diets is adequate to achieve optimal efficacy with fixed-dose artemether-lumefantrine: a review of the evidence

Abstract A fixed-dose combination of artemether-lumefantrine (AL, Coartem®) has shown high efficacy, good tolerability and cost-effectiveness in adults and children with uncomplicated malaria caused by Plasmodium falciparum. Lumefantrine bioavailability is enhanced by food, particularly fat. As the fat content of sub-Saharan African meals is approximately a third that of Western countries, it raises the question of whether fat consumption by African patients is sufficient for good efficacy. Data from healthy volunteers have indicated that drinking 36 mL soya milk (containing only 1.2 g of fat) results in 90% of the lumefantrine absorption obtained with 500 mL milk (16 g fat). African diets are typically based on a carbohydrate staple (starchy root vegetables, fruit [plantain] or cereals) supplemented by soups, relishes and sauces derived from vegetables, pulses, nuts or fish. The most important sources of dietary fat in African countries are oil crops (e.g. peanuts, soya beans) and cooking oils as red palm, peanut, coconut and sesame oils. Total fat intake in the majority of subSaharan countries is estimated to be in the range 30–60 g/person/day across the whole population (average 43 g/person/day). Breast-feeding of infants up to two years of age is standard, with one study estimating a fat intake of 15–30 g fat/day from breast milk up to the age of 18 months. Weaning foods typically contain low levels of fat, and the transition from breast milk to complete weaning is associated with a marked reduction in dietary fat. Nevertheless, fat intake >10 g/day has been reported in young children post-weaning. A randomized trial in Uganda reported no difference in the efficacy of AL between patients receiving supervised meals with a fixed fat content (~23 g fat) or taking AL unsupervised, suggesting that fat intake at home was sufficient for optimal efficacy. Moreover, randomized trials in African children aged 5–59 months have shown similar high cure rates to those observed in older populations, indicating that food consumption is adequate post-weaning. In conclusion, it appears that only a very small amount of dietary fat is necessary to ensure optimal efficacy with AL and that the fat content of standard meals or breast milk in sub-Saharan Africa is adequate.</p

How do fatalistic beliefs affect the attitudes and pedestrian behaviours of road users in different countries? A cross-cultural study

This paper reports on an exploratory investigation of the influence of five different types of fatalistic belief constructs (namely divine control, luck, helplessness, internality, and general fatalism) on three classes of self-reported pedestrian behaviours (memory and attention errors, rule violations, and aggressive behaviours) and on respondents’ general attitudes to road safety, and how relationships between constructs differ across countries. A survey of over 3,400 respondents across Bangladesh, China, Kenya, Thailand, the UK, and Vietnam revealed a similar pattern for most of the relationships assessed, in most countries; those who reported higher fatalistic beliefs or more external attributions of causality also reported performing riskier pedestrian behaviours and holding more dangerous attitudes to road safety. The strengths of relationships between constructs did, however, differ by country, behaviour type, and aspect of fatalism. One particularly notable country difference was that in Bangladesh and, to a lesser extent, in Kenya, a stronger belief in divine influence over one’s life was associated with safer attitudes and behaviours, whereas where significant relationships existed in the other countries the opposite was true. In some cases, the effect of fatalistic beliefs on self-reported behaviours was mediated through attitudes, in other cases the effect was direct. Results are discussed in terms of the need to consider the effect of locus of control and attributions of causality on attitudes and behaviours, and the need to understand the differences between countries therei

Plasma nevirapine concentrations predict virological and adherence failure in Kenyan HIV-1 infected patients with extensive antiretroviral treatment exposure

Treatment failure is a key challenge in the management of HIV-1 infection. We conducted a mixed-model survey of plasma nevirapine (NVP) concentrations (cNVP) and viral load in order to examine associations with treatment and adherence outcomes among Kenyan patients on prolonged antiretroviral therapy (ART). Blood plasma was collected at 1, 4 and 24 hours post-ART dosing from 58 subjects receiving NVP-containing ART and used to determine cNVP and viral load (VL). Median duration of treatment was 42 (range, 12–156) months, and 25 (43.1%) of the patients had virologic failure (VF). cNVP was significantly lower for VF than non- VF at 1hr (mean, 2,111ng/ml vs. 3,432ng/ml, p = 0.003) and at 4hr (mean 1,625ng/ml vs. 3,999ng/ml, p = 0.001) but not at 24hr post-ART dosing. Up to 53.4%, 24.1% and 22.4% of the subjects had good, fair and poor adherence respectively. cNVP levels peaked and were > = 3μg.ml at 4 hours in a majority of patients with good adherence and those without VF. Using a threshold of 3μg/ml for optimal therapeutic nevirapine level, 74% (43/58), 65.5% (38/58) and 86% (50/58) of all patients had sub-therapeutic cNVP at 1, 4 and 24 hours respectively. cNVP at 4 hours was associated with adherence (p = 0.05) and virologic VF (p = 0.002) in a chi-square test. These mean cNVP levels differed significantly in non-parametric tests between adherence categories at 1hr (p = 0.005) and 4hrs (p = 0.01) and between ART regimen categories at 1hr (p = 0.004) and 4hrs (p<0.0001). Moreover, cNVP levels correlated inversely with VL (p< = 0.006) and positively with adherence behavior. In multivariate tests, increased early peak NVP (cNVP4) was independently predictive of lower VL (p = 0.002), while delayed high NVP peak (cNVP24) was consistent with increased VL (p = 0.033). These data strongly assert the need to integrate plasma concentrations of NVP and that of other ART drugs into routine ART management of HIV-1 patients