Conventional, Complementary and Alternative Medicines: Mechanistic Insights into Therapeutic Landscape of Chronic Obstructive Pulmonary Disease

: COPD (chronic obstructive pulmonary disease) is a major public health concern associated with significant morbidity and mortality worldwide. Current therapeutic guidelines for this disease recommend starting with an inhaled bronchodilator, stepping up to combination therapy as necessary, and/or adding inhaled corticosteroids as symptoms and airflow obstruction progress. However, no drug therapy exists to stop disease progression. The mechanistic definition underlying COPD pathogenesis remains poorly understood, it is generally accepted that oxidative stress and the altered immune response of low-grade airway inflammation are major factors contributing to COPD development. There are several potential therapeutic targets that are currently under investigation, including immune regulatory pathways in inflammation and lung-associated steroid resistance induced by oxidative stress signaling cascades. Patients with COPD have increased levels of inflammatory mediators, including lipid and peptide mediators, as well as a network of cytokines and chemokines that maintain inflammatory immune response and recruit circulating cells into the lungs. Many of these proinflammatory mediators are regulated by nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinases (MAPKs), such as p38 MAPK. Increased oxidative stress is a key driving mechanism in perpetuating inflammation and lung injury. Furthermore, many proteases that degrade elastin fibres are secreted by airway resident infiltrating immune cells in COPD patients. In this perspective, we discuss novel aspects of signaling pathway activation in the context of inflammation and oxidative stress, and the broad view of potential effective pharmacotherapies that target the underlying mechanistic disease process in COPD

Comparison of Digital 12-Lead ECG and Digital 12-Lead Holter ECG Recordings in Healthy Male Subjects: Results from a Randomized, Double-Blinded, Placebo-Controlled Clinical Trial

Background Electrocardiogram (ECG) variability is greatly affected by the ECG recording method. This study aims to compare Holter and standard ECG recording methods in terms of central locations and variations of ECG data. Methods We used the ECG data from a double-blinded, placebo-controlled, randomized clinical trial and used a mixed model approach to assess the agreement between two methods in central locations and variations of eight ECG parameters (Heart Rate, PR, QRS, QT, RR, QTcB, QTcF, and QTcI intervals). Results A total of 34 heathy male subjects with mean age of 25.7 ± 4.78 years were randomized to receive either active drug or placebo. Digital 12-lead ECG and digital 12-lead Holter ECG recordings were performed to assess ECG variability. There are no significant differences in least square mean between the Holter and the standard method for all ECG parameters. The total variance is consistently higher for the Holter method than the standard method for all ECG parameters except for QRS. The intraclass correlation coefficient (ICC) values for the Holter method are consistently lower than those for the standard method for all ECG parameters except for QRS, in particular, the ICC for QTcF is reduced from 0.86 for the standard method to 0.67 for the Holter method. Conclusions This study suggests that Holter ECGs recorded in a controlled environment are not significantly different but more variable than those from the standard method

Levofloxacin can be used effectively as a positive control in thorough QT/QTc studies in healthy volunteers

center dot New drugs are expected to undergo rigorous clinical electrocardiographic evaluation ('thorough QT/QTc study') during their early clinical development in order to determine any affect on cardiac repolarization. center dot The fluoroquinolone antibiotic moxifloxacin (400 mg) has been used as a positive comparator for thorough QT/QTc studies due to its QT prolongation (QTcF) of between 6 and 10 ms. center dot Positive comparators that are able to produce mean changes close to the regulatory guidelines of 5 ms, and which can be detected by the assay in use, would enable a more rigorous evaluation of the assay conditions used in evaluating new chemical entities. WHAT THIS STUDY ADDS center dot This thorough QT/QTc study directly compares the effects of two doses of levofloxacin and moxifloxacin on QTc in the same healthy subjects. center dot Mean QTc was prolonged in subjects receiving levofloxacin compared with placebo as determined by both individual and Fridericia's heart rate correction methods. center dot The largest time-matched differences in QTc for two doses of levofloxacin compared with placebo suggest the potential for using levofloxacin in more rigorous QT/QTc studies, providing a robust evaluation of the assay conditions used in determining potential effects on cardiac repolarization. center dot There is evidence to suggest that levofloxacin moderately increases heart rate in a dose-dependent fashion. AIMS To characterize the effects of levofloxacin on QT interval in healthy subjects and the most appropriate oral positive control treatments for International Conference on Harmonization (ICH) E14 QT/QTc studies. METHODS Healthy subjects received a single dose of levofloxacin (1000 or 1500 mg), moxifloxacin (400 mg) or placebo in a four-period crossover design. Digital 12-lead ECGs were recorded in triplicate. Measurement of QT interval was performed automatically with subsequent manual onscreen over-reading using electronic callipers. Blood samples were taken for determination of levofloxacin and moxifloxacin concentrations. RESULTS Mean QTcI (QT interval corrected for heart rate using a correction factor that is applicable to each individual) was prolonged in subjects receiving moxifloxacin 400 mg compared with placebo. The largest time-matched difference in QTcI for moxifloxacin compared with placebo was observed to be 13.19 ms (95% confidence interval 11.21, 15.17) at 3.5 h post dose. Prolonged mean QTcI was also observed in subjects receiving levofloxacin 1000 mg and 1500 mg compared with placebo. The largest time-matched difference in QTcI compared with placebo was observed at 3.5 h post dose for both 1000 mg and 1500 mg of levofloxacin [mean (95%) 4.42 ms (2.44, 6.39) in 1000 mg and 7.44 ms (5.47, 9.42) in 1500 mg]. A small increase in heart rate was observed with levofloxacin during the course of the study. However, moxifloxacin showed a greater increase compared with levofloxacin. CONCLUSIONS Both levofloxacin and moxifloxacin can fulfil the criteria for a positive comparator. The ICH E14 guidelines recommend a threshold of around 5 ms for a positive QT/QTc study. The largest time-matched difference in QTc for levofloxacin suggests the potential for use in more rigorous QT/QTc studies. This study has demonstrated the utility of levofloxacin on the assay in measuring mean QTc changes around 5 ms

Investigation of the association between lens autofluorescence ratio and diabetes: a cross-sectional study.

Lens autofluorescence ratio (LFR) is a novel approach to detect advanced glycation end products in a time-saving and non-invasive manner. However, its associations with glycemia and diabetes remain unclear. We conducted this study to address this issue in Chinese adults. We enrolled a total of 4,705 participants aged 20-70 years in China between May 2020 and January 2021 in a cross-sectional study. LFR was determined by biomicroscopy (ClearPath DS-120). Diabetes was ascertained by oral glucose tolerance test, self-reported history, and/or antidiabetic medication use. Correlation and logistic regression analyses were performed. LFR was higher in participants with diabetes than those without (23.27 ± 6.51 vs. 19.45 ± 5.08, p < 0.001). LFR correlated with fasting plasma glucose and hemoglobin A1c in the overall and diabetes-stratified populations. The odds of diabetes was increased by 6% per one percent higher of LFR after multivariable-adjustment (odds ratio (OR) 1.06, 95% CI 1.04-1.08, p < 0.001). Participants in the highest quartile of LFR had higher odds of diabetes compared with those in the lowest quartile (OR 1.83, 95% CI 1.33-2.52, p < 0.001). Mediation analysis showed that, insulin resistance, as assessed by triglyceride-glucose index, may underline the relationship between high LFR and increased odds of diabetes. LFR, a non-invasive indirect measure of advanced glycation end products, appears to be associated with glycemia and the risk of developing diabetes in Chinese adults

Comparison of six commonly used QT correction models and their parameter estimation methods.

This paper compares six commonly used QT correction models and three available parameter estimation methods using five indices for QTc evaluation based on real and simulated electrocardiograph (ECG) datasets. The results show that the golden section approach always finds the correction factor making QTc interval uncorrelated to heart rate for all six formulas. However, the correction formulas derived from mixed model sometimes fail to make QTc interval invariant of heart rate. The performance of an individual least-square regression method lies between the golden section iteration approach and the mixed model in terms of QTc-RR relationship

A nonparametric approach to QT interval correction for heart rate.

We propose to use generalized additive models to fit the relationship between QT interval and RR (RR = 60/heart rate), and develop two new methods for correcting the QT for heart rate: the linear additive model and log-transformed linear additive model. The proposed methods are compared with six commonly used parametric models that were used in four clinical trial data sets and a simulated data set. The results show that the linear additive models provide the best fit for the vast majority of individual QT-RR profiles. Moreover, the QT correction formula derived from the linear additive model outperforms other correction methods