Effect of folic acid and metformin on insulin resistance and inflammatory factors of obese children and adolescents

Background: Considering the increasing trend of obesity, especially in developing countries such as Iran, and the role of inflammatory factors and insulin resistance (IR) in the occurrence of obesity-related complications as well as the safety of some agents such as folic acid and metformin, this clinical trial was designed to investigate the effect of metformin and folic acid on inflammatory factors and IR among obese children. Materials and Methods: In this randomized, double-blind, controlled clinical trial study, sixty obese children aged 6-12 years were enrolled. Selected obese children were randomly allocated in two interventional (1 mg/daily folic acid or 1000 mg metformin for 8 weeks) groups. Biochemical measurements including homeostasis model assessment of IR (HOMA-IR), homocysteine (Hcy), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8) were measured between and within the groups before and after trial. Results: In each group, thirty obese children were studied. The groups were age- and sex-matched. After folic acid and metformin administration, mean of Hcy, HOMA-IR, TNF-α, and IL-8 decreased significantly (P < 0.05). IL-6 decreased significantly after folic acid use (P < 0.05). Conclusion: The findings of this trial indicated that both metformin and folic acid could decrease IR and level of Hcy in obese children and adolescents. The effectiveness of metformin on IR was more significant than folic acid. Regarding the effectiveness of the two studied agents on inflammatory factors, it is suggested that the role of folic acid was superior to metformin. It is suggested that metformin is a proper agent for obese children with IR and folic acid is an appropriate supplement for obese children with increased inflammatory factors. © 2016 Journal of Research in Medical Sciences

Interventions to improve adherence to inhaled steroids for asthma.

BACKGROUND: Despite its proven efficacy in improving symptoms and reducing exacerbations, many patients with asthma are not fully adherent to their steroid inhaler. Suboptimal adherence leads to poorer clinical outcomes and increased health service utilisation, and has been identified as a contributing factor to a third of asthma deaths in the UK. Reasons for non-adherence vary, and a variety of interventions have been proposed to help people improve treatment adherence. OBJECTIVES: To assess the efficacy and safety of interventions intended to improve adherence to inhaled corticosteroids among people with asthma. SEARCH METHODS: We identified trials from the Cochrane Airways Trials Register, which contains studies identified through multiple electronic searches and handsearches of other sources. We also searched trial registries and reference lists of primary studies. We conducted the most recent searches on 18 November 2016. SELECTION CRITERIA: We included parallel and cluster randomised controlled trials of any duration conducted in any setting. We included studies reported as full-text articles, those published as abstracts only and unpublished data. We included trials of adults and children with asthma and a current prescription for an inhaled corticosteroid (ICS) (as monotherapy or in combination with a long-acting beta2-agonist (LABA)). Eligible trials compared an intervention primarily aimed at improving adherence to ICS versus usual care or an alternative intervention. DATA COLLECTION AND ANALYSIS: Two review authors screened the searches, extracted study characteristics and outcome data from included studies and assessed risk of bias. Primary outcomes were adherence to ICS, exacerbations requiring at least oral corticosteroids and asthma control. We graded results and presented evidence in 'Summary of findings' tables for each comparison.We analysed dichotomous data as odds ratios, and continuous data as mean differences or standardised mean differences, all using a random-effects model. We described skewed data narratively. We made no a priori assumptions about how trials would be categorised but conducted meta-analyses only if treatments, participants and the underlying clinical question were similar enough for pooling to make sense. MAIN RESULTS: We included 39 parallel randomised controlled trials (RCTs) involving adults and children with asthma, 28 of which (n = 16,303) contributed data to at least one meta-analysis. Follow-up ranged from two months to two years (median six months), and trials were conducted mainly in high-income countries. Most studies reported some measure of adherence to ICS and a variety of other outcomes such as quality of life and asthma control. Studies generally were at low or unclear risk of selection bias and at high risk of biases associated with blinding. We considered around half the studies to be at high risk for attrition bias and selective outcome reporting.We classified studies into four comparisons: adherence education versus control (20 studies); electronic trackers or reminders versus control (11 studies); simplified drug regimens versus usual drug regimens (four studies); and school-based directly observed therapy (three studies). Two studies are described separately.All pooled results for adherence education, electronic trackers or reminders and simplified regimens showed better adherence than controls. Analyses limited to studies using objective measures revealed that adherence education showed a benefit of 20 percentage points over control (95% confidence interval (CI) 7.52 to 32.74; five studies; low-quality evidence); electronic trackers or reminders led to better adherence of 19 percentage points (95% CI 14.47 to 25.26; six studies; moderate-quality evidence); and simplified regimens led to better adherence of 4 percentage points (95% CI 1.88 to 6.16; three studies; moderate-quality evidence). Our confidence in the evidence was reduced by risk of bias and inconsistency.Improvements in adherence were not consistently translated into observable benefit for clinical outcomes in our pooled analyses. None of the intervention types showed clear benefit for our primary clinical outcomes - exacerbations requiring an oral corticosteroid (OCS) (evidence of very low to low quality) and asthma control (evidence of low to moderate quality); nor for our secondary outcomes - unscheduled visits (evidence of very low to moderate quality) and quality of life (evidence of low to moderate quality). However, some individual studies reported observed benefits for OCS and use of healthcare services. Most school or work absence data were skewed and were difficult to interpret (evidence of low quality, when graded), and most studies did not specifically measure or report adverse events.Studies investigating the possible benefit of administering ICS at school did not measure adherence, exacerbations requiring OCS, asthma control or adverse events. One study showed fewer unscheduled visits, and another found no differences; data could not be combined. AUTHORS' CONCLUSIONS: Pooled results suggest that a variety of interventions can improve adherence. The clinical relevance of this improvement, highlighted by uncertain and inconsistent impact on clinical outcomes such as quality of life and asthma control, is less clear. We have low to moderate confidence in these findings owing to concerns about risk of bias and inconsistency. Future studies would benefit from predefining an evidence-based 'cut-off' for acceptable adherence and using objective adherence measures and validated tools and questionnaires. When possible, covert monitoring and some form of blinding or active control may help disentangle effects of the intervention from effects of inclusion in an adherence trial

Warfarin dose requirement and cytochrome P450 2C9 and Vitamin K epoxide reductase complex subunit 1-1639 genetic polymorphisms in Thai patients

Aims: The purposes of this study were to investigate the influence of genetic polymorphisms of cytochrome P450 2C9 (CYP2C9)FNx013 and Vitamin K epoxide reductase complex subunit 1-1639 (VKORC1-1639) G >A and patient′s characteristics on warfarin dose requirement and to establish an equation for predicting the warfarin maintenance dose in Thai patients. Settings and Design: This is an observational, retrospective study in outpatients. Ninety-one outpatients receiving warfarin at Phaholpolpayuhasena Hospital, Kanchanaburi, were recruited to this study. Subjects and Methods: Whole blood, dose, and demographic data were collected. Blood samples were analyzed for the genetic polymorphism by restriction fragment length polymorphism technique. Statistical Analysis Used: Differences in baseline characteristics among genotypes were evaluated by analysis of variance or Kruskal-Wallis and the Mann-Whitney U-test or Chi-square test for parametric and nonparametric variables, respectively. Association between genetic factors and warfarin dose was based on Eta test, whereas associations between warfarin dose and polymorphisms were evaluated using Pearson correlation test. Stepwise regression was used to identify factors contributing to warfarin dose requirement followed by linear regression model to develop a warfarin dosing algorithm. Results: CYP2C9FNx011FNx011 (wild type) genotype was found in 90 patients (98.90%), and CYP2C9FNx011FNx013 was found in only 1 patient (1.10%). No CYP2C9FNx013FNx013 genotype was observed. Polymorphisms of VKORC1-1639 GG was found in 9 patients (9.89%) while GA and AA genotype were found in 30 patients (32.97%) and in 52 patients (57.14%), respectively. Patients with VKORC1-1639 AA genotype required statistically and significantly lower, average weekly warfarin dose (19.97 ± 7.61 mg) than GG genotype (37.89 ± 12.20 mg) and GA genotype (29.48 ± 11.50 mg) with the P < 0.05. Conclusions: Using stepwise multiple linear regression, VKORC1-1639 AA, age, and weight could explain about 45.3% of the variation of warfarin maintenance dose. Multivariate analysis of the equation indicated a significant negative correlation between warfarin dose and VKORC1-1639 AA and age, but a significant positive correlation between warfarin dose and weight. This suggested that VKORC1 genotyping may be more important in warfarin dose adjustment and should be a priority for genotype measurement

The Synergistic Activity and Optimizing Doses of Tigecycline in Combination with Aminoglycosides against Clinical Carbapenem-Resistant Klebsiella pneumoniae Isolates

Carbapenem-resistant Enterobacteriaceae (CRE), especially carbapenem-resistant Klebsiella pneumoniae (CRKP), are among the largest pathogenic threats to humans. The available antibiotic treatment options for combating CRKP are limited. Colistin-resistant Enterobacteriaceae (CoRE) have also been reported worldwide, including in Thailand. Therefore, this study aimed (1) to determine minimum inhibitory concentrations (MICs) and synergistic activities of antibiotics of CRKP, and (2) to determine the probability target of attainment (PTA) and cumulative fraction of response (CFR) using pharmacokinetic/pharmacodynamic (PK/PD) data. Clinical CRKP isolates were obtained from Phramongkutklao Hospital (June to November 2020). Broth microdilution and checkerboard techniques were used to determine the mono- and synergistic activities of antibiotics. Carbapenemase and mcr-1 genes were also identified by polymerase chain reaction (PCR). The optimal antibiotic regimens were evaluated using Monte Carlo simulations. Forty-nine CRKP isolates were collected, 40 of which were CoRKP strains. The MIC50 and MIC90 of tigecycline, amikacin, and gentamicin were 1 and 2 µg/mL, 4 and 16 µg/mL, and 0.25 and 4 µg/mL, respectively. None of any isolates expressed the mcr-1 gene, whereas blaOXA-48 (53.1%) and blaOXA-48 plus blaNDM (42.9%) were detected. Synergistic activity was observed in 8.2% of isolates for tigecycline combined with amikacin or gentamicin. Additive activity was observed in 75.5% of isolates for tigecycline-amikacin and 69.4% for tigecycline-gentamicin, and no antagonism was observed. High-dose antibiotic regimens achieved the PTA target. The general recommended dose of combination regimens began with 200 mg tigecycline and 25 mg/kg amikacin, or 7 mg/kg gentamicin, followed by 100 mg tigecycline every 12 h and 15 mg/kg amikacin or 5 mg/kg gentamicin every 24 h. In conclusion, tigecycline plus aminoglycosides might be a potential regimen against CRKP and CoRKP. The appropriate combination regimen based on MIC-based dose adjustment can improve optimal antibiotic dosing. Further research via clinical studies will be necessary to confirm these results

Correction: Nulsopapon et al. The Synergistic Activity and Optimizing Doses of Tigecycline in Combination with Aminoglycosides against Clinical Carbapenem-Resistant <i>Klebsiella pneumoniae</i> Isolates. <i>Antibiotics</i> 2021, <i>10</i>, 736

There were errors made in the original article [...

Impaired insulin signaling affects renal organic anion transporter 3 (Oat3) function in streptozotocin-induced diabetic rats.

Organic anion transporter 3 (Oat3) is a major renal Oats expressed in the basolateral membrane of renal proximal tubule cells. We have recently reported decreases in renal Oat3 function and expression in diabetic rats and these changes were recovered after insulin treatment for four weeks. However, the mechanisms by which insulin restored these changes have not been elucidated. In this study, we hypothesized that insulin signaling mediators might play a crucial role in the regulation of renal Oat3 function. Experimental diabetic rats were induced by a single intraperitoneal injection of streptozotocin (65 mg/kg). One week after injection, animals showing blood glucose above 250 mg/dL were considered to be diabetic and used for the experiment in which insulin-treated diabetic rats were subcutaneously injected daily with insulin for four weeks. Estrone sulfate (ES) uptake into renal cortical slices was examined to reflect the renal Oat3 function. The results showed that pre-incubation with insulin for 30 min (short term) stimulated [3H]ES uptake into the renal cortical slices of normal control rats. In the untreated diabetic rats, pre-incubation with insulin for 30 min failed to stimulate renal Oat3 activity. The unresponsiveness of renal Oat3 activity to insulin in the untreated diabetic rats suggests the impairment of insulin signaling. Indeed, pre-incubation with phosphoinositide 3-kinase (PI3K) and protein kinase C zeta (PKCζ) inhibitors inhibited insulin-stimulated renal Oat3 activity. In addition, the expressions of PI3K, Akt and PKCζ in the renal cortex of diabetic rats were markedly decreased. Prolonged insulin treatment in diabetic rats restored these alterations toward normal levels. Our data suggest that the decreases in both function and expression of renal Oat3 in diabetes are associated with an impairment of renal insulin-induced Akt/PKB activation through PI3K/PKCζ/Akt/PKB signaling pathway