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Peter J Barnes - One of the best experts on this subject based on the ideXlab platform.
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treatment effects of low dose Theophylline combined with an inhaled corticosteroid in copd
Chest, 2010Co-Authors: Paul Ford, Richard Russell, Andrew L Durham, Fabiana Gordon, Ian M Adcock, Peter J BarnesAbstract:Background Inhaled corticosteroids (ICS) have proved disappointing at reducing airway inflammation in COPD. However, previous studies indicate that low doses of Theophylline enhance the activity of a key corticosteroid-associated corepressor protein, histone deacetylase (HDAC)2, which is reduced in COPD. This may account, at least in part, for the relative corticosteroid resistance. Thus, combination therapy with an ICS and low-dose Theophylline may be of benefit in the treatment of COPD. Methods To test the hypothesis that ICS and Theophylline have a greater therapeutic effect than Theophylline alone, 30 patients with COPD were treated with placebo Theophylline capsules and either inhaled fluticasone propionate (FP) (500 μg bid) or inhaled placebo for 4 weeks in a double-dummy, randomized, double-blind, parallel study. After a 2-week washout, patients were given active Theophylline capsules (plasma level of 8.8–12.4 mg/L). Results In an across-arm comparison, combination treatment with FP and Theophylline did not reduce total sputum neutrophils but significantly reduced total sputum eosinophils ( P P 1 % predicted ( P P Conclusions Combination therapy with an inhaled corticosteroid and low-dose Theophylline may attenuate airway inflammation in patients with COPD. Trial registration clinicaltrials.gov ; Identifier NCT00241631
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Theophylline in chronic obstructive pulmonary disease new horizons
Proceedings of the American Thoracic Society, 2005Co-Authors: Peter J BarnesAbstract:Although Theophylline has side effects when used in bronchodilator doses, increasing evidence shows that it has significant antiinflammatory effects in chronic obstructive pulmonary disease at lower plasma concentrations. These antiinflammatory effects are unlikely to be accounted for by phosphodiesterase inhibition or adenosine receptor antagonism, which require higher concentrations. There is now evidence that Theophylline at low therapeutic concentrations is an activator of histone deacetylases and that this activation enhances the antiinflammatory effect of corticosteroids. There appears to be a marked reduction in histone deacetylase-2 in macrophages and peripheral lung of patients with chronic obstructive pulmonary disease, which accounts for amplified inflammation and steroid resistance. Theophylline has been shown to restore steroid sensitivity in vitro. The effect of Theophylline on histone deacetylase activity appears to be enhanced by oxidative stress. The mechanism whereby Theophylline activates histone deacetylase is not yet known, but it does not involve other known actions of Theophylline that account for its side effects. Better understanding of the molecular basis for the action of Theophylline might lead to the development of novel drugs.
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a molecular mechanism of action of Theophylline induction of histone deacetylase activity to decrease inflammatory gene expression
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Kazuhiro Ito, Ian M Adcock, Sam Lim, Gaetano Caramori, Borja G Cosio, Fan K Chung, Peter J BarnesAbstract:The molecular mechanism for the anti-inflammatory action of Theophylline is currently unknown, but low-dose Theophylline is an effective add-on therapy to corticosteroids in controlling asthma. Corticosteroids act, at least in part, by recruitment of histone deacetylases (HDACs) to the site of active inflammatory gene transcription. They thereby inhibit the acetylation of core histones that is necessary for inflammatory gene transcription. We show both in vitro and in vivo that low-dose Theophylline enhances HDAC activity in epithelial cells and macrophages. This increased HDAC activity is then available for corticosteroid recruitment and predicts a cooperative interaction between corticosteroids and Theophylline. This mechanism occurs at therapeutic concentrations of Theophylline and is dissociated from phosphodiesterase inhibition (the mechanism of bronchodilation) or the blockade of adenosine receptors, which are partially responsible for its side effects. Thus we have shown that low-dose Theophylline exerts an anti-asthma effect through increasing activation of HDAC which is subsequently recruited by corticosteroids to suppress inflammatory genes.
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effect of Theophylline on induced sputum inflammatory indices and neutrophil chemotaxis in chronic obstructive pulmonary disease
American Journal of Respiratory and Critical Care Medicine, 2002Co-Authors: Sarah V Culpitt, Carmen De Matos, Richard Russell, Louise E Donnelly, Duncan F Rogers, Peter J BarnesAbstract:Chronic obstructive pulmonary disease (COPD) is characterized by a neutrophilic airway inflammation that can be demonstrated by examination of induced sputum. Theophylline has antiinflammatory effects in asthma, and in the present study we investigated whether a similar effect occurs in COPD patients treated with low doses of Theophylline. Twenty-five patients with COPD were treated with Theophylline (plasma level of 9–11 mg/L) for 4 weeks in a placebo-controlled, randomized, double-blind crossover study. Theophylline was well tolerated. Induced sputum inflammatory cells, neutrophils, interleukin-8, myeloperoxidase, and lactoferrin were all significantly reduced by about 22% by Theophylline. Neutrophils from subjects treated with Theophylline showed reduced chemotaxis to N-formyl-met-leu-phe (∼ 28%) and interleukin-8 (∼ 60%). Neutrophils from a healthy donor showed reduced chemotaxis (∼ 30%) to induced sputum samples obtained during Theophylline treatment. These results suggest that Theophylline has antii...
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immunomodulation by Theophylline in asthma demonstration by withdrawal of therapy
American Journal of Respiratory and Critical Care Medicine, 1995Co-Authors: J C Kidney, M Dominguez, P M Taylor, Marlene L Rose, Kian Fan Chung, Peter J BarnesAbstract:Theophylline is the most widely used anti-asthma drug worldwide and is classified as a bronchodilator, although there is increasing evidence that it may have immunomodulatory effects. We have investigated the effects of Theophylline withdrawal under placebo control in 27 asthmatic patients (25 to 70 yr) treated with long-term Theophylline who were also treated with high dose inhaled corticosteroids. We measured asthma symptoms (diary card), lung function (spirometry and home records of peak expiratory flow), and peripheral leukocyte populations using dual color flow cytometry. In eight of these patients, we examined fiberoptic bronchial biopsies by immunocytochemistry. We also studied peripheral blood lymphocytes in eight asthmatic patients who have never received Theophylline. Mean steady state plasma Theophylline concentrations during Theophylline therapy were 8.6 +/- 0.9 mg/L. Theophylline withdrawal was associated with a significant increase in asthma symptoms, particularly at night, and a fall in spirometry and morning peak flow. This was accompanied by a significant fall in peripheral blood monocytes (CD14+, activated CD4+ T-lymphocytes (CD4+/CD25+) and activated CD8+ T-cells (CD8+/HLA-DR+) in patients with a plasma Theophylline > 5 mg/L. The lymphocyte populations in Theophylline-naive patients were similar to those found after Theophylline withdrawal. Bronchial biopsies showed a mirror image of the peripheral blood with an increase in CD4+ and CD8+ lymphocytes in the airway. Chronic treatment with Theophylline, even at low plasma concentrations, controls asthma symptoms and has effects on T-lymphocyte populations in the peripheral blood which are the inverse of those observed in the airways.(ABSTRACT TRUNCATED AT 250 WORDS)
Taliang Chen - One of the best experts on this subject based on the ideXlab platform.
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alteration of the pharmacokinetics of Theophylline by rutaecarpine an alkaloid of the medicinal herb evodia rutaecarpa in rats
Journal of Pharmacy and Pharmacology, 2005Co-Authors: Yune-fang Ueng, Rueiming Chen, Tunghu Tsai, Taliang ChenAbstract:Rutaecarpine is a main active alkaloid present in the medicinal herb, Evodia rutaecarpa. The cytochrome P450 (CYP) 1A2 substrate, Theophylline, is an important therapeutic agent for the treatment of asthma, but has a narrow therapeutic index. To evaluate the pharmacokinetic interaction of Theophylline with rutaecarpine, the effects of rutaecarpine on CYP1A2 activity and Theophylline pharmacokinetics were investigated. Oral treatment of Sprague-Dawley rats with 50mgkg ---1 rutaecarpine for three days through a gastrogavage caused a 4- and 3-fold increase in liver microsomal 7-ethoxyresorufin O-deethylation (EROD) and 7-methoxyresorufin O-demethylation activity, respectively. In the kidney, rutaecarpine treatment caused a 3-fold increase in EROD activity. In the lungs, EROD activity was elevated from an undetectable to a detectable level by rutaecarpine. Pharmacokinetic parameters of Theophylline were determined using a microdialysis sampling method. Rutaecarpine pre-treatment increased the clearance of Theophylline in a dose-dependent manner. Pre-treatment of rats with 50mgkg ---1 rutaecarpine caused a 3-fold increase in Theophylline clearance and a 70%, 68% and 68% decrease in the area under the concentration–time curve (AUC), mean residence time (MRT) and half-life, respectively. These results demonstrated that rutaecarpine treatment elevated CYP1A2 catalytic activity and Theophylline excretion in rats. In patients taking Theophylline, adverse effects might be noticed when a rutaecarpine-containing herbal preparation is used concomitantly.
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alteration of the pharmacokinetics of Theophylline by rutaecarpine an alkaloid of the medicinal herb evodia rutaecarpa in rats
Journal of Pharmacy and Pharmacology, 2005Co-Authors: Yune-fang Ueng, Rueiming Chen, Tunghu Tsai, Taliang ChenAbstract:Rutaecarpine is a main active alkaloid present in the medicinal herb, Evodia rutaecarpa. The cytochrome P450 (CYP) 1A2 substrate, Theophylline, is an important therapeutic agent for the treatment of asthma, but has a narrow therapeutic index. To evaluate the pharmacokinetic interaction of Theophylline with rutaecarpine, the effects of rutaecarpine on CYP1A2 activity and Theophylline pharmacokinetics were investigated. Oral treatment of Sprague-Dawley rats with 50mgkg ---1 rutaecarpine for three days through a gastrogavage caused a 4- and 3-fold increase in liver microsomal 7-ethoxyresorufin O-deethylation (EROD) and 7-methoxyresorufin O-demethylation activity, respectively. In the kidney, rutaecarpine treatment caused a 3-fold increase in EROD activity. In the lungs, EROD activity was elevated from an undetectable to a detectable level by rutaecarpine. Pharmacokinetic parameters of Theophylline were determined using a microdialysis sampling method. Rutaecarpine pre-treatment increased the clearance of Theophylline in a dose-dependent manner. Pre-treatment of rats with 50mgkg ---1 rutaecarpine caused a 3-fold increase in Theophylline clearance and a 70%, 68% and 68% decrease in the area under the concentration–time curve (AUC), mean residence time (MRT) and half-life, respectively. These results demonstrated that rutaecarpine treatment elevated CYP1A2 catalytic activity and Theophylline excretion in rats. In patients taking Theophylline, adverse effects might be noticed when a rutaecarpine-containing herbal preparation is used concomitantly.
Imoigele P Aisiku - One of the best experts on this subject based on the ideXlab platform.
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association of pre hospital Theophylline use and mortality in chronic obstructive pulmonary disease patients with sepsis
Respiratory Medicine, 2017Co-Authors: Yuning Shih, Yung Tai Chen, Hsi Chu, Chiajen Shih, Yentao Hsu, Ranchou Chen, Sadeq A Quraishi, Imoigele P AisikuAbstract:Abstract Background Although Theophylline has been shown to have anti-inflammatory effects, the therapeutic use of Theophylline before sepsis is unknown. The aim of our study was to determine the effect of Theophylline on COPD patients presenting with sepsis. Methods This nationwide, population-based, propensity score-matched analysis used data from the linked administrative databases of Taiwan's National Health Insurance program. Patients with COPD who were hospitalized for sepsis between 2000 and 2011 were divided into Theophylline users and non-users. The primary outcome was 30-day mortality. The secondary outcome was in-hospital death, intensive care unit admission, and need for mechanical ventilation. Cox proportional hazard model and conditional logistic regression were used to calculate the risk between groups. Results A propensity score-matched cohort of 51,801 Theophylline users and 51,801 non-users was included. Compared with non-users, the 30-day (HR 0.931, 95% CI 0.910–0.953), 180-day (HR 0.930, 95% CI 0.914–0.946), 365-day (HR 0.944, 95% CI 0.929–0.960) and overall mortality (HR 0.965, 95% CI 0.952–0.979) were all significantly lower in Theophylline users. Additionally, the Theophylline users also had lower risk of in-hospital death (OR 0.895, 95% CI 0.873–0.918) and need for mechanical ventilation (OR 0.972, 95% CI 0.949–0.997). Conclusions Theophylline use is associated with a lower risk of sepsis-related mortality in COPD patients. Pre-hospital Theophylline use may be protective to COPD patients with sepsis.
Yune-fang Ueng - One of the best experts on this subject based on the ideXlab platform.
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alteration of the pharmacokinetics of Theophylline by rutaecarpine an alkaloid of the medicinal herb evodia rutaecarpa in rats
Journal of Pharmacy and Pharmacology, 2005Co-Authors: Yune-fang Ueng, Rueiming Chen, Tunghu Tsai, Taliang ChenAbstract:Rutaecarpine is a main active alkaloid present in the medicinal herb, Evodia rutaecarpa. The cytochrome P450 (CYP) 1A2 substrate, Theophylline, is an important therapeutic agent for the treatment of asthma, but has a narrow therapeutic index. To evaluate the pharmacokinetic interaction of Theophylline with rutaecarpine, the effects of rutaecarpine on CYP1A2 activity and Theophylline pharmacokinetics were investigated. Oral treatment of Sprague-Dawley rats with 50mgkg ---1 rutaecarpine for three days through a gastrogavage caused a 4- and 3-fold increase in liver microsomal 7-ethoxyresorufin O-deethylation (EROD) and 7-methoxyresorufin O-demethylation activity, respectively. In the kidney, rutaecarpine treatment caused a 3-fold increase in EROD activity. In the lungs, EROD activity was elevated from an undetectable to a detectable level by rutaecarpine. Pharmacokinetic parameters of Theophylline were determined using a microdialysis sampling method. Rutaecarpine pre-treatment increased the clearance of Theophylline in a dose-dependent manner. Pre-treatment of rats with 50mgkg ---1 rutaecarpine caused a 3-fold increase in Theophylline clearance and a 70%, 68% and 68% decrease in the area under the concentration–time curve (AUC), mean residence time (MRT) and half-life, respectively. These results demonstrated that rutaecarpine treatment elevated CYP1A2 catalytic activity and Theophylline excretion in rats. In patients taking Theophylline, adverse effects might be noticed when a rutaecarpine-containing herbal preparation is used concomitantly.
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alteration of the pharmacokinetics of Theophylline by rutaecarpine an alkaloid of the medicinal herb evodia rutaecarpa in rats
Journal of Pharmacy and Pharmacology, 2005Co-Authors: Yune-fang Ueng, Rueiming Chen, Tunghu Tsai, Taliang ChenAbstract:Rutaecarpine is a main active alkaloid present in the medicinal herb, Evodia rutaecarpa. The cytochrome P450 (CYP) 1A2 substrate, Theophylline, is an important therapeutic agent for the treatment of asthma, but has a narrow therapeutic index. To evaluate the pharmacokinetic interaction of Theophylline with rutaecarpine, the effects of rutaecarpine on CYP1A2 activity and Theophylline pharmacokinetics were investigated. Oral treatment of Sprague-Dawley rats with 50mgkg ---1 rutaecarpine for three days through a gastrogavage caused a 4- and 3-fold increase in liver microsomal 7-ethoxyresorufin O-deethylation (EROD) and 7-methoxyresorufin O-demethylation activity, respectively. In the kidney, rutaecarpine treatment caused a 3-fold increase in EROD activity. In the lungs, EROD activity was elevated from an undetectable to a detectable level by rutaecarpine. Pharmacokinetic parameters of Theophylline were determined using a microdialysis sampling method. Rutaecarpine pre-treatment increased the clearance of Theophylline in a dose-dependent manner. Pre-treatment of rats with 50mgkg ---1 rutaecarpine caused a 3-fold increase in Theophylline clearance and a 70%, 68% and 68% decrease in the area under the concentration–time curve (AUC), mean residence time (MRT) and half-life, respectively. These results demonstrated that rutaecarpine treatment elevated CYP1A2 catalytic activity and Theophylline excretion in rats. In patients taking Theophylline, adverse effects might be noticed when a rutaecarpine-containing herbal preparation is used concomitantly.
Timothy J. Sullivan - One of the best experts on this subject based on the ideXlab platform.
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steady state pharmacokinetics of Theophylline in copd patients treated with dirithromycin
The Journal of Clinical Pharmacology, 1993Co-Authors: Kenneth Bachmann, Luis Jauregui, Gregory D Sides, Timothy J. SullivanAbstract:: Steady-state Theophylline pharmacokinetic parameters were studied in a panel of 14 patients with chronic obstructive pulmonary disease (COPD). Pharmacokinetic parameters were evaluated before, during, and after a 10-day regimen of the macrolide antibiotic, dirithromycin. The addition of dirithromycin (500 mg orally once daily at 7:00 AM) to a sustained-release Theophylline dosing regimen (every 12 hours) elicited small changes in the steady-state pharmacokinetics of Theophylline, which were not statistically significant. Mean steady-state plasma Theophylline trough concentrations (Css,min) were invariant before, during, and after dirithromycin treatment. Mean average steady-state plasma Theophylline concentrations (Cav) declined by 7% during dirithromycin treatment (NS), and mean peak plasma concentrations (Css,max) declined by 12% (NS). Theophylline clearance (CL/F) also remained relatively unchanged during dirithromycin treatment exhibiting an increase of only 11% (NS). Dirithromycin treatment does not significantly affect the steady-state pharmacokinetics of Theophylline, and its use in COPD patients is not likely to modify treatment outcomes with Theophylline.
