RESUMO
Type 2 diabetes mellitus (T2DM) is a growing public health challenge for Thailand (current prevalence ~10.0%). Amino acids offer novel biomarkers to predict risk of T2DM and indicate sub-optimal disease management, which could facilitate earlier treatment. We studied amino acid profiles in a Thai cohort comprising of individuals with T2DM (n = 65 single-drug-treated; n = 38 multi-drug-treated) compared to healthy controls (n = 104) using liquid chromatography-mass spectrometry. Age and BMI were significantly lower in the healthy controls compared to the single or multi-treated T2DM groups. The BCAA (leucine and valine) were significantly lower in the single and multi-treated T2DM groups compared to healthy controls (p < 0.001 and p < 0.001) and isoleucine was significantly lower in the single-treated compared to the healthy controls (p = 0.014). These findings beg the question whether BCAAs supplementation be beneficial in T2DM patients treated with single or multi-drug therapy? Tyrosine was significantly lower in the single and multi-treated T2DM groups compared to healthy controls (p < 0.001 and p = 0.002), whereas phenylalanine was significantly higher in the multi-treated T2DM group compared to the single treated T2DM group (p = 0.045). We provide novel insights into the effects of diabetes treatments on these amino acids in insulin resistant states such as T2DM in a unique but understudied Thai population.
RESUMO
BACKGROUND: Safe, cheap and effective adjunct therapies preventing the development of, or reducing the mortality from, severe malaria could have considerable and rapid public health impact. Oral activated charcoal (oAC) is a safe and well tolerated treatment for acute poisoning, more recently shown to have significant immunomodulatory effects in man. In preparation for possible efficacy trials in human malaria, we sought to determine whether oAC would i) reduce mortality due to experimental cerebral malaria (ECM) in mice, ii) modulate immune and inflammatory responses associated with ECM, and iii) affect the pharmacokinetics of parenteral artesunate in human volunteers. METHODS/PRINCIPAL FINDINGS: We found that oAC provided significant protection against P. berghei ANKA-induced ECM, increasing overall survival time compared to untreated mice (p<0.0001; hazard ratio 16.4; 95% CI 6.73 to 40.1). Protection from ECM by oAC was associated with reduced numbers of splenic TNF(+) CD4(+) T cells and multifunctional IFNgamma(+)TNF(+) CD4(+) and CD8(+) T cells. Furthermore, we identified a whole blood gene expression signature (68 genes) associated with protection from ECM. To evaluate whether oAC might affect current best available anti-malarial treatment, we conducted a randomized controlled open label trial in 52 human volunteers (ISRCTN NR. 64793756), administering artesunate (AS) in the presence or absence of oAC. We demonstrated that co-administration of oAC was safe and well-tolerated. In the 26 subjects further analyzed, we found no interference with the pharmacokinetics of parenteral AS or its pharmacologically active metabolite dihydroartemisinin. CONCLUSIONS/SIGNIFICANCE: oAC protects against ECM in mice, and does not interfere with the pharmacokinetics of parenteral artesunate. If future studies succeed in establishing the efficacy of oAC in human malaria, then the characteristics of being inexpensive, well-tolerated at high doses and requiring no sophisticated storage would make oAC a relevant candidate for adjunct therapy to reduce mortality from severe malaria, or for immediate treatment of suspected severe malaria in a rural setting. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN64793756.