Efficacy and side effects of intravenous theophylline in acute asthma: a systematic review and meta-analysis

Gulixian Mahemuti, Hui Zhang, Jing Li, Nueramina Tieliwaerdi, Lili Ren Respiratory Department, The Second Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Province, People’s Republic of China Background and objective: Theophylline has been used for decades to treat both acute and chronic asthma. Despite its longevity in the practitioner’s formulary, no detailed meta-analysis has been performed to determine the conditions, including concomitant medications, under which theophylline should be used for acute exacerbations of asthma. We aimed to quantify the usefulness and side effects of theophylline with or without ethylene diamine (aminophylline) in acute asthma, with particular emphasis on patient subgroups, such as children, adults, and concomitant medications.Methods: We searched PubMed, EMBASE, The Cochrane Library, ClinicalTrials.gov, and the WHO Clinical Trials Registry for randomized, controlled clinical trials. We planned a priori subgroup analyses by time post-medication, concomitant medication, control type, and age.Results: We included 52 study arms from 42 individual trials. Of these, 29 study arms included an active control, such as adrenaline, beta-2 agonists, or leukotriene receptor antagonists, and 23 study arms compared theophylline (with or without ethylene diamine) with placebo or no drug. Theophylline significantly reduced heart rate when compared with active control (p=0.01) and overall duration of stay (p=0.002), but beta-2 agonists were superior to theophylline at improving forced expiratory volume in one second (FEV1) (p=0.002). Theophylline was not significantly different from other drugs in its effects on respiratory rate, forced vital capacity (FVC), peak expiratory flow rate, admission rate, use of rescue medication, oxygen saturation, or symptom score. Closer examination of the data revealed that the medications given in addition to theophylline or control significantly changed the effectiveness of theophylline (subgroup difference: p<0.00001).Conclusion: Given the low cost of theophylline, and its similar efficacy and rate of side effects compared with other drugs, we suggest that theophylline, when given with bronchodilators with or without steroids, is a cost-effective and safe choice for acute asthma exacerbations. Keywords: theophylline, theophylline with ethylene diamine, aminophylline, asthma, bronchodilators, beta-2 agonists, adrenaline, FEV, PEFR, affordable drug

Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts

Experimental and/or epidemiological studies suggest that prenatal exposure to bisphenol A (BPA) may delay fetal lung development and maturation and increase the susceptibility to childhood respiratory disease. However, the underlying mechanisms remain to be elucidated. In our previous study with cultured human fetal lung fibroblasts (HFLF), we demonstrated that 24-h exposure to 1 and 100 µM BPA increased GPR30 protein in the nuclear fraction. Exposure to 100 μM BPA had no effects on cell viability, but increased cytoplasmic expression of ERβ and release of GDF-15, as well as decreased release of IL-6, ET-1, and IP-10 through suppression of NFκB phosphorylation. By performing global gene expression and pathway analysis in this study, we identified molecular pathways, gene networks, and key molecules that were affected by 100, but not 0.01 and 1 µM BPA in HFLF. Using multiple genomic and proteomic tools, we confirmed these changes at both gene and protein levels. Our data suggest that 100 μM BPA increased CYP1B1 and HSD17B14 gene and protein expression and release of endogenous estradiol, which was associated with increased ROS production and DNA double-strand breaks, upregulation of genes and/or proteins in steroid synthesis and metabolism, and activation of Nrf2-regulated stress response pathways. In addition, BPA activated ATM-p53 signaling pathway, resulting in increased cell cycle arrest at G1 phase, senescence and autophagy, and decreased cell proliferation in HFLF. The results suggest that prenatal exposure to BPA at certain concentrations may affect fetal lung development and maturation, and thereby affecting susceptibility to childhood respiratory diseases