Effects of doxofylline as an adjuvant on severe exacerbation and long-term prognosis for COPD with different clinical subtypes.

OBJECTIVE: This study aimed to investigate the effectiveness of doxofylline as an adjuvant in reducing severe exacerbation for different clinical subtypes of chronic obstructive pulmonary disease (COPD). METHODS: The clinical trial was an open-label non-randomized clinical trial that enrolled patients with COPD. The patients were divided into two groups (doxofylline group[DG] and non-doxofylline group[NDG]) according to whether the adjuvant was used. Based on the proportion of inflammatory cells present, the patients were divided into neutrophilic, eosinophilic, and mixed granulocytic subtypes. The rates of severe acute exacerbation, use of glucocorticoids, and clinical symptoms were followed up in the first month, the third month, and the sixth month after discharge. RESULTS: A total of 155 participants were included in the study. The average age of the participants was 71.2 ± 10.1 years, 52.3% of the patients were male, and 29.7% of the participants had extremely severe cases of COPD. In the third month after discharge the numbers of patients exhibiting severe exacerbation among the neutrophilic subtype were 5 (6.6%) in the DG versus 17 (22.4%) in the NDG (incidence rate ratio[IRR] = 0.4 [95% CI: 0.2-0.9] P = 0.024). In the sixth month after discharge, the numbers were 3 (3.9%) versus 13 (17.1%; IRR = 0.3 [95%; CI: 0.1-0.9], P = 0.045), and those for the eosinophilic subtype were 0 (0.0%) versus 4 (14.8%), P = 0.02. In the eosinophilic subtype, the results for forced expiratory volume in the first second and maximal mid-expiratory flow were significantly higher in the DG. The mean neutrophil and eosinophil levels were significantly lower than in the NDG among the neutrophilic subtype, and the neutrophil percentage was lower than in the NDG among the eosinophilic subtype. At the six-month follow-up, the dose adjustment rates of the neutrophilic and eosinophilic subtypes showed a significant difference (P< 0.05). CONCLUSIONS: As an adjuvant drug, doxofylline has a good therapeutic effect on patients with the neutrophilic and eosinophilic clinical subtypes of COPD. It can reduce the incidence of severe exacerbation, the use of glucocorticoids, and inflammatory reactions in the long term (when used for a minimum of 3 months).

Relationship between atmospheric pollutants and risk of death caused by cardiovascular and respiratory diseases and malignant tumors in Shenyang, China, from 2013 to 2016: an ecological research.

BACKGROUND: Air pollutants and their pathogenic effects differ among regions and seasons. We aimed to explore the relationship between fine particulate matter (PM2.5), sulfur dioxide (SO2), and ozone-8 hours (O3-8h) concentrations in heating and non-heating seasons and the associated death risk due to cardiovascular diseases (CDs), respiratory diseases (RDs), and malignant tumors. METHODS: Data were collected in Shenyang, China, from April 2013 to March 2016. We analyzed the correlation or lagged effect of atmospheric pollutant concentration, meteorological conditions, and death risk due to disorders of the circulatory system, respiratory system, and malignant tumor in heating and non-heating seasons. We also used multivariate models to analyze the association of air pollutants during holidays with the death risk due to the evaluated diseases while considering the presence or absence of meteorological factors. RESULTS: An increase in the daily average SO2 concentration by 10 µg/m increased the death risk by CDs, which reached a maximum of 2.0% (95% confidence interval [CI]: 1.3%-2.7%) on lagging day 4 during the non-heating season and 0.2% (95% CI: 0.1%-0.4%) on lagging day 3 during the heating season. The risk of death caused by RDs peaked on lagging day 1 by 0.8% (95% CI: 0.4%-1.2%) during the heating season. An increase in O3-8h concentration by 10 µg/m increased the risk of RD-related death on lagging day 2 by 1.0% (95% CI: 0.4%-1.7%) during the non-heating season, which was significantly higher than the 0.1% (95% CI: 0-0.9%) increase during the heating season. Further, an increase in the daily average PM2.5 concentration by 10 µg/m increased the risk of death caused by RDs by 0.3% and 0.8% during heating and non-heating seasons, respectively, which peaked on lagging day 0. However, air pollution was not significantly associated with the risk of death caused by malignant tumors. CONCLUSION: Short-term exposure to PM2.5, SO2, and O3 during the non-heating season resulted in higher risks of CD-related death, followed by RD-related death.

Development and validation of a UPLC-MS/MS method for quantification of doxofylline and its metabolites in human plasma.

A sensitive and specific ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for simultaneous determination of doxofylline and its two metabolites in human plasma. After protein precipitation with methanol, the chromatographic separation was carried out on an ACQUITY UPLC HSS T3 column, with acetonitrile and 0.1% formic acid in water as mobile phase at a flow rate of 0.30 mL·min-1. The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) mode via electrospray ionization (ESI) source, with target quantitative ion pairs of m/z 267.0→181.1 for doxofylline, 239.0→181.1 for theophylline-7-acetic acid and 225.1→181.1 for etofylline. The calibration curve was linear over the range of 2-3000 ng·mL-1 (r > 0.99). The LLOQ was evaluated to be 2 ng·mL-1. The method described herein allowed simultaneous determination of the three analytes for the first time and was successfully applied to the pharmacokinetic study of doxofylline and its metabolites after intravenous administration in healthy volunteers.

Cx37 C1019T polymorphism may contribute to the pathogenesis of coronary heart disease.

OBJECTIVE: We conducted a meta-analysis of case-control studies to evaluate whether Cx37 C1019T (rs1764391 C>T) polymorphism may be implicated in the pathogenesis of coronary heart disease (CHD). METHODS: The MEDLINE (1966-2013), the Cochrane Library Database (Issue 12, 2013), EMBASE (1980-2013), CINAHL (1982-2013), Web of Science (1945-2013), and the Chinese Biomedical Database (CBM) (1982-2013) were searched without language restrictions. Meta-analysis was performed with the use of the STATA statistical software. Odds ratios (ORs) with their 95% confidence intervals (95% CIs) were calculated. RESULTS: Nine case-control studies with a total of 1426 CHD patients and 929 healthy controls met the inclusion criteria. Our results revealed that Cx37 C1019T polymorphism might be significantly correlated with the risk of CHD (T allele vs. C allele: OR=1.63, 95% CI=1.20-2.21, p=0.002; CT+TT vs. CC: OR=1.86, 95% CI=1.28-2.69, p=0.001; TT vs. CC+CT: OR=1.81, 95% CI=1.24-2.64, p=0.002; TT vs. CC: OR=2.50, 95% CI=1.46-4.27, p=0.001; TT vs. CT: OR=1.53, 95% CI=1.12-2.09, p=0.008; respectively). Further subgroup analysis by country indicated that Cx37 C1019T polymorphism might be closely linked to an increased risk of CHD among Chinese populations, while no positive associations were observed among non-Chinese populations (all p>0.05). CONCLUSION: Our findings provide empirical evidence that Cx37 C1019T polymorphism may contribute to the pathogenesis of CHD, especially among Chinese populations.

[The effect of simvastatin on alveolar epithelial cells in cigarette smoking-induced emphysema].

OBJECTIVE: to explore the effect of simvastatin on alveolar epithelial cells and the expression of vascular endothelial growth factor (VEGF) in cigarette smoking-induced emphysema in rats. METHODS: twenty-four, 12-week-old healthy male and female Wistar rats were randomly divided into 4 groups of 6 each: a control (W) group, a smoking (Sm) group, a simvastatin (St) group, and a smoking-simvastatin (SmSt) group. The rats were simultaneously fed, and kept in individual cages for 16 weeks. The VEGF level in lung tissue and bronchoalveolar lavage fluid (BALF) of each group was measured by ELISA. The expression of VEGF mRNA was determined by RT-PCR. The expressions of VEGF and proliferating cell nuclear antigen (PCNA) were determined by two-step immunohistochemistry assay. One-way ANOVA and LSD-t test were used for statistical analysis. RESULTS: the percentage of PCNA-positively stained alveolar epithelial cells was significantly higher in the SmSt group [(10.3 ± 2.0)%] than in the Sm group [(4.8 ± 0.8)%]. The levels of VEGF in BALF and lung tissue homogenate of the SmSt group [(187 ± 15) ng/L and (6782 ± 50) ng/L] were similar to the W group [(200 ± 20) ng/L and (7558 ± 330) ng/L], but were significantly higher than that in the Sm group [(71 ± 16) ng/L and (4149 ± 110) ng/L]. VEGF expression in alveolar and bronchial epithelial cells of rats in the SmSt group [(67.7 ± 5.0)% and (49.0 ± 3.0)%], was similar to the W group [(68.3 ± 3.3)% and (51.3 ± 2.9)%]. But the level of VEGF expression was significantly increased as compared to that in the Sm group [(27.0 ± 5.9)% and (16.3 ± 2.7)%]. SmSt group vs Sm group t = 1.117 - 12.001, all P < 0.01. CONCLUSIONS: simvastatin ameliorated the development of cigarette smoke-induced COPD in rats, partly by promoting alveolar epithelial cell proliferation and up-regulating the expression of VEGF.

Vascular endothelial injuries and changes of blood coagulation and fibrinolysis indexes in patients with acute respiratory distress syndrome.

OBJECTIVE: To study endothelial damage by observing changes of circulating endothelial cells (CECs) in blood, coagulation and fibrinolysis index in patients with acute respiratory distress syndrome. METHODS: CECs were separated by isopycnic centrifugation method in 14 patients with acute lung injury (ALI), 7 patients with acute respiratory distress syndrome (ARDS), 10 intensive care unit (ICU) controls, and 15 healthy controls. Plasma prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FG), fibrin degradation products (FDP), and D-dimer were examined simultaneously. Acute physiology and chronic health evaluation (APACHE) II and lung injury score (LIS) were recorded to evaluate severity of illness and lung injury. RESULTS: (1) The number of CECs in ALI (10.4 +/- 2.3) and ARDS groups (16.1 +/- 2.7) was higher than that in the healthy (1.9 +/- 0.5) (P < 0.01). In both ALI and ARDS, the number of CECs correlated with APACHE II (r = 0.55, P < 0.05 and r = 0.62, P < 0.05, respectively) and LIS (r = 0.60, P < 0.05 and r = 0.53, P < 0.05, respectively). CEC number was negatively correlated with PaO2 in ALI and ARDS (r = -0.49, P < 0.05 and r = -0.64, P < 0.05, respectively). (2) The level of FDP and D-dimer were higher in ALI and ARDS patients than that in ICU and healthy control groups (P < 0.05). The level of FG in ARDS group was significantly higher than in the ICU and healthy control groups (P < 0.05). But in ALI group, the level of FG was significantly higher than only healthy control group (P < 0.05). CONCLUSIONS: Endothelial cell damage occurs in ARDS patients, which may play a major role in the pathophysiology of ARDS. Changes of endothelial cell activation and damage markers, such as CECs, plasma coagulation and fibrinolysis index, to some extent reflect severity of illness and lung injury in ARDS.