Bethesda, MD 20894, Web Policies After a 2 week run-in period subjects attended for FEV1 and histamine PD20 followed 1 h later by AMP PD20 measurement. Accessibility Persson C.G.A. Withdrawal symptoms occurred in normal subjects when their caffeine intake was stopped for 24 h [].Whether a withdrawal syndrome occurs with theophylline, a related xanthine, is unknown but worsening asthma control has been reported following cessation of theophylline in case reports and controlled studies [2-4].Although theophylline has several actions recent work suggests . Yasui K., Agematsu K., Shinozaki K., Hokibara S., Nagumo H., Nakazawa T., Komiyama A. Theophylline induces neutrophil apoptosis through adenosine A. Ohta K., Yamashita N. Apoptosis of eosinophils and lymphocytes in allergic inflammation. Theophylline is a methylxanthine, similar in structure to the common dietary xanthines caffeine and theobromine. FEV1 was measured as the higher of two readings within 100 ml (c Vitalograph Ltd, Bucks, UK). Theophylline has several cellular effects that may contribute to its clinical efficacy in the treatment of asthma (Figure 3). A more gradual increase in theophylline dose may have improved compliance but would not have allowed us to compare lung function after the first and last dose. Duffy N., Walker P., Diamantea F., Calverley P.M., Davies L. Intravenous aminophylline in patients admitted to hospital with non-acidotic exacerbations of chronic obstructive pulmonary disease: A prospective randomised controlled trial. Barnes P.J. Barnes P.J., Adcock I.M., Ito K. Histone acetylation and deacetylation: Importance in inflammatory lung diseases. Theophylline (dimethylxanthine) has been used to treat airway diseases for more than 80 years. Owing to the withdrawal of some of the patients in the nonsurgical arms, the mean follow-up period was longer in the pacemaker . government site. It has been suggested that theophylline may exert its effects in asthma via some action outside the airways. Intravenous aminophylline has been used for many years in the treatment of acute severe asthma. Doxofylline (7-(1,3-dioxalan-2-yl-methyl) theophylline) has similar efficacy to theophylline but has less effect on adenosine receptors so fewer cardiovascular and central side effects [5]. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (, Phosphodiesterase inhibition (non-selective), Inhibition of nuclear factor-B ( nuclear translocation), Inhibition of phosphoinositide 3 kinase-, poly(ADP-ribose)polymerase-1 (inhibits cell death), Histone deacetylase activity ( efficacy of corticosteroids), Enzyme induction (rifampicin, phenobarbitone, ethanol), Enzyme inhibition (cimetidine, erythromycin, ciprofloxacin, allopurinol, zileuton), methylxanthine, phosphodiesterase, adenosine receptor, histone deacetylase, bronchodilatation, inflammation, immunomodulation, plasma concentration, drug interaction. Because of problems with side effects, there have been attempts to improve on theophylline and recently there has been increasing interest in selective phosphodiesterase (PDE) inhibitors, which have the possibility of improving the beneficial and reducing the adverse effects of theophylline. Wenzel S.E., Szefler S.J., Leung D.Y., Sloan S.I., Rex M.D., Martin R.J. Bronchoscopic evaluation of severe asthma. On Jeanneau, Dufour or Beneteau only the top and more expensive yachts use a sandwich hull. Theophylline discontinuation resulted in a gradual increase in BP and an urgent call for antihypertensive treatment modification. PD20 AMP was measured before treatment and 9 h after the final dose. Correspondence: Dr J. Polosa R., Blackburn M.R. Interleukin(IL)-10 has a broad spectrum of anti-inflammatory effects and there is evidence that its secretion is reduced in asthma and COPD [21]. Low-dose theophylline reduces eosinophilic inflammation but not exhaled nitric oxide in mild asthma. The .gov means its official. It was originally used as a bronchodilator but the relatively high doses required are associated with frequent side effects, so its use declined as inhaled 2 -agonists became more widely used. Efficacy and safety profile of xanthines in COPD: a network meta-analysis. Approved as a pharmacy medicine, Sanofi will launch Cialis Together in the second half of the year. Federal government websites often end in .gov or .mil. It was originally used as a bronchodilator, but the relatively high doses required are associated with frequent side effects, so its use declined as inhaled 2-agonists became more widely used.More recently it has been shown to have antiinflammatory effects in asthma and chronic obstructive . Nielson C.P., Crawley J.J., Morgan M.E., Vestal R.E. There may also be increased acid secretion, gastroesophageal reflux and diuresis. However these effects are less than those expected with low doses of inhaled corticosteroids and there is no reduction of exhaled nitric oxide, indicating a lesser effect on suppression of inflammation than corticosteroids. Thus, if a patient on maintenance theophylline requires a course of erythromycin, the dose of theophylline should be halved. Orange R.P., Kaliner M.A., Laraia P.J., Austen K.F. Anhydrous theophylline has the chemical name 1H-Purine- 2,6-dione, 3,7-dihydro-1 ,3 -dimethyl-, and is represented by the following structural formula: . Schrier D.J., Imre R.M. In a controlled trial of theophylline withdrawal in patients with severe asthma controlled only on high doses of inhaled corticosteroids, there was a significant deterioration in symptoms and lung function when placebo was substituted for the relatively low maintenance dose of theophylline [83]. More recently it has been shown to have anti-inflammatory effects in asthma and COPD at lower concentrations. Theophylline has a stimulatory effect on suppressor (CD8+) T-lymphocytes, which may be relevant to the control of chronic airway inflammation [75,76], and has an inhibitory effect on graft rejection [77]. Before Accessibility Miura M., Belvisi M.G., Stretton C.D., Yacoub M.H., Barnes P.J. Aminophylline toxicity - how many hospital asthma deaths does it cause? Ward A.J.M., McKenniff M., Evans J.M., Page C.P., Costello J.F. This would mean that theophylline might have a greater inhibitory effect on PDE in asthmatic airways than in normal airways. Stimulatory and inhibitory regulation of calcium-activated potassium channels by guanine nucleotide binding proteins. There is convincing in vitro evidence that theophylline relaxes airway smooth muscle by inhibition of PDE activity, but relatively high concentrations are needed for maximal relaxation [7]. Careers, Unable to load your collection due to an error. Management of asthma and chronic airflow limitation. In patients with acute asthma, intravenous aminophylline is less effective than nebulized 2-agonists [93], and should therefore be reserved for those who fail to respond to -agonists. Bowler S.D., Mitchell C.A., Armstrong J.G. There is also evidence that addition of theophylline improves asthma control to a greater extent than 2-agonists in patients with severe asthma treated with high dose inhaled steroids [102]. Intravenous aminophylline has been used in the management of acute severe asthma for over 50 years, but this use has been questioned in view of the risk of adverse effects compared with nebulized 2-agonists. This suggests that low dose theophylline may find an important place in the management in patients of patients with severe asthma and all patients with COPD. Chronic treatment with low dose theophylline reduces the numbers of eosinophils in bronchial biopsies, bronchoalveolar lavage and induced sputum of patients with mild asthma [61]. Magnussen H., Reuss G., Jrres R. Methylxanthines inhibit exercise-induced bronchoconstriction at low serum theophylline concentrations and in a dose-dependent fashion. Bachelet M., Vincent D., Havet N., Marrash-Chahla R., Pradalier A., Dry J., Vargaftig B.B. Drug dosage was then adjusted by an independent investigator using a computer programme (Pharmacy Department, City Hospital, Nottingham) to maintain theophylline levels in the therapeutic range (1020 mg l1). IL-10 release is increased by theophylline and this effect may be mediated via PDE inhibition [22], although this has not been seen at the low doses that are effective in asthma [23]. government site. Bethesda, MD 20894, Web Policies Influence of cellular levels of cyclic AMP. Fink G., Mittelman M., Shohat B., Spitzer S.A. Theophylline-induced alterations in cellular immunity in asthmatic patients. Would you like email updates of new search results? For continuous treatment, twice daily therapy (approximately 8 mg/kg twice daily) is needed, although some preparations are designed for once daily administration. Effect of theophylline on induced sputum inflammatory indices and neutrophil chemotaxis in COPD. Evans D.J., Taylor D.A., Zetterstrom O., Chung K.F., O'Connor B.J., Barnes P.J. Evidence in vitro supports this hypothesis; Torphy et al. Multiple cellular effects of theophylline. T-lymphocytes are now believed to play a central role in coordinating the chronic inflammatory response in asthma. Theophylline induces apoptosis of T-lymphocytes, thus reducing their survival [32]. However, theophylline is a less effective option than adding a long-acting inhaled 2-agonist [99]. Time course of change in bronchial reactivity with an inhaled corticosteroid in asthma. (85 pages) Boat Bavaria 36 2010 Information & Operation Manual. DESCRIPTION CIALIS (tadalafil), an oral treatment for erectile dysfunction, is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). UK. Kobayashi M., Nasuhara Y., Betsuyaku T., Shibuya E., Tanino Y., Tanino M., Takamura K., Nagai K., Hosokawa T., Nishimura M. Effect of low-dose theophylline on airway inflammation in COPD. Both slow-release aminophylline and theophylline are available and are equally effective (although the ethylene diamine component of aminophylline has very occasionally been implicated in allergic reactions). Theophylline also appears to reduce the formation of peroxynitrite and this provides a further mechanism for increasing HDAC2 function in asthma [45]. It was originally used as a bronchodilator but the relatively high doses required are associated with frequent side effects, so its use declined as inhaled 2-agonists became more widely used. The response of these patients to withdrawal of theophylline therapy suggests that the clinical effectiveness of this drug cannot be explained exclusively by bronchodilation. Cushley M.J., Holgate S.T. However, 2-agonists cause bronchodilatation, at least in part, by opening maxi-K channels in airway smooth muscle cells [48]. Theophylline is given systemically (orally as slow-release preparations for chronic treatment and intravenously for acute exacerbations of asthma) and blood concentrations are determined mainly by hepatic metabolism, which may be increased or decreased in several diseases and by concomitant drug therapy. Barnes P.J. As a library, NLM provides access to scientific literature. Lam A., Newhouse M.T. Murciano D, Auclair MH, Pariente R, Aubier M. N Engl J Med. The bronchodilator effect of theophylline in chronic asthma is small in comparison with 2-agonists, however. This process is reversed by the recruitment of histone deacetylases (HDAC) to the activated inflammatory gene promoter site within the nucleus. Adenosine-induced bronchoconstriction in asthma: Antagonism by inhaled theophylline. Theophylline therapy was continued in 20 patients and replaced by placebo from day 3 on in the remainder; measurements were repeated on days 5 and 6. The mechanism of bronchoconstriction is indirect and involves release of histamine from airway mast cells [14,19]. Withdrawal of theophylline therapy resulted in significant (p < 0.05) deterioration in lung function, exercise performance, and two indices of overall dyspnea, and a significant increase in scoring of symptoms and auscultation findings. Comparison of addition of theophylline to inhaled steroid with doubling of the dose of inhaled steroid in asthma. Guillot C., Fornaris M., Badger M., Orehek J. Spontaneous and provoked resistance to isoproterenol in isolated human bronchi. MeSH Shuster L. Repression and de-repression of enzyme synthesis as a possible explanation of some aspects of drug action. It is well tolerated when given twice daily by mouth. Brenner M, Berkowitz R, Marshall N, Strunk RC. Role of potassium channels in bronchodilator responses in human airways. Theophylline is used to treat the symptoms of asthma or other lung conditions that block your airways, such as emphysema or chronic bronchitis. Mean change in FEV1 and PD20 histamine values 8 h following the first and last dose of treatment and the mean minimum FEV1 and PD20 histamine value following withdrawal of treatment (32 and 56 h) were compared between theophylline and placebo by paired t-test. In airways obtained at lung surgery approximately 25% of preparations fail to relax with a -agonist, but all relax with theophylline [47]. 19.79. Angina can be "stable" or "unstable." Angina is unstable when there is a change in the usual pattern, such as a change in frequency, occurrence with less exertion, or occurrence at rest. Adenosine induced bronchoconstriction in asthma: Role of mast cell mediator release. The mechanism of action of theophylline in nocturnal asthma may involve more than long-lasting bronchodilatation, and could involve inhibition of some components of the inflammatory response, which may increase at night [69]. official website and that any information you provide is encrypted Jatakanon A., Uasaf C., Maziak W., Lim S., Chung K.F., Barnes P.J. Federal government websites often end in .gov or .mil. baseline characteristics of subjects prior to starting placebo and theophylline. Currie GP, Butler CA, Anderson WJ, Skinner C. Br J Clin Pharmacol. Smaller Hanse models are now built with single skin (monolithic skin), the 418 is the first with a sandwich-hull but the new 458 comes with a single skin hull and only bigger boats have a sandwich-hull. After day 20, fungi count maintained a high level overt 1.0 10 5 CFU/g. Kidney J, Dominguez M, Taylor PM, Rose M, Fan Chung K, Barnes PJ. The site is secure. This may be particularly appropriate in patients with more severe asthma in whom corticosteroids are less effective as there may be a reduction in HDAC activity in these patients [37] as well as in smoking asthmatics patients [109] and patients with COPD [114]. Addition of intravenous aminophylline to beta2-agonists in adults with acute asthma. It also reduces nitrative stress in macrophages from patients with COPD, whereas high doses of an inhaled corticosteroid are without effect [45]. Our data show that about half of the patients with severe COPD can be considered as theophylline responders. Lim S., Groneberg D., Fischer A., Oates T., Caramori G., Mattos W., Adcock I., Barnes P.J., Chung K.F. Theophylline also has an inhibitory effect on superoxide anion release from human neutrophils [56] and inhibits the feedback stimulatory effect of adenosine on neutrophils in vivo [57]. Theophylline is a weak bronchodilator at therapeutically relevant concentrations, suggesting that some other target cell may be more relevant for its anti-asthma effect. State of play (29 pages) Boat Bavaria Cruiser 46 Owner's Manual. Following withdrawal of theophylline there were significantly lower values for mean FEV1 (mean difference 0.15 l, 95% CI 0.03, 026) and PD20 AMP compared to placebo but no difference in other end points. However, PDE activity may be increased in asthmatic airways as a result of inflammation so that theophylline may have a greater than expected effect. This indicates that aminophylline should not be added routinely to nebulized -agonists. Minimum FEV1 values were significantly lower following withdrawal of theophylline compared with placebo (mean difference 0.15 [95% CI 0.03 to 0.26] l) (Table 2). Magnusson H., Reuss G., Jorres R. Theophylline has a dose-related effect on the airway response to inhaled histamine and methacholine in asthmatics. Pharmacological treatment of chronic obstructive pulmonary disease. Mechanism of airway hyperresponsiveness to adenosine induced by allergen challenge in actively sensitized Brown Norway rats. Effect of theophylline on induced sputum inflammatory indices in COPD patients. Need for theophylline in severe steroid-dependent asthmatics. Thus total PDE activity in human lung extracts is inhibited by only 510% by therapeutic concentrations of theophylline [6]. Decreased histone deacetylase activity in chronic obstructive pulmonary disease. The dose of theophylline required to give therapeutic concentrations varies among patients, largely because of differences in clearance. Theophylline inhibits neutrophil chemotaxis via inhibition of adenosine A2A-receptors and this may be relevant in severe asthma [62]. II. 2006;1(4):409-23. doi: 10.2147/copd.2006.1.4.409. Development of safer xanthine drugs for the treatment of obstructive airways disease. If this occurred following regular theophylline treatment a transient increase in intracellular cAMP degradation with a rebound deterioration in lung function would be expected following drug withdrawal. Immunomodulation by theophylline in asthma: Demonstration by withdrawal of therapy. Vathenen AS. Theophylline is a xanthine derivative that is used both orally or intravenously in the treatment of apnea of prematurity and as an adjunct agent for patients with asthma. This effect is not mediated via PDE inhibition, but in neutrophils may be mediated by antagonism of adenosine A2A-receptors [31]. These effects are seen even in patients treated with high doses of inhaled corticosteroids, indicating that the molecular effects of theophylline are likely to be different from those of corticosteroids. Effect of theophylline and adenosine on eosinophil function. However, these effects are seen at high concentrations and may be mediated by inhibition of PDE. 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Like email updates of new search results now believed to play a central role in the! Of mast cell mediator release exercise-induced bronchoconstriction at low serum theophylline concentrations and in a dose-dependent....