Theophylline

The leaves of Black tea.

Theophylline is a methylated xanthine derivative; competitive nonselective phosphodiesterase inhibitor and nonselective adenosine receptor antagonist.

References:
[1]. Deree J, et al. Insights into the regulation of TNF-alpha production in human mononuclear cells: the effects of non-specific phosphodiesterase inhibition. Clinics (Sao Paulo). 2008 Jun;63(3):321-8. [2]. Marques LJ, et al. Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages. Am J Respir Crit Care Med. 1999 Feb;159(2):508-11. [3]. Daly JW, et al. Adenosine receptors: development of selective agonists and antagonists. Prog Clin Biol Res. 1987;230:41-63.

Comparative study of the efficacy and safety of theophylline and doxofylline in patients with bronchial asthma and chronic obstructive pulmonary disease.[Pubmed:25894641]

J Basic Clin Physiol Pharmacol. 2015 Sep;26(5):443-51.

BACKGROUND: Bronchial asthma and chronic obstructive pulmonary disease (COPD) are the major obstructive disorders that may contribute to the severity in individual patients. The present study was designed to compare the efficacy and safety of Theophylline and doxofylline in patients with bronchial asthma and COPD. METHODS: A total of 60 patients, 30 each with bronchial asthma and COPD, were enrolled for the study. Each group of 30 patients received standard treatment for asthma and COPD. Each group was again subdivided into two with 15 patients each, who received Theophylline or doxofylline in addition to standard therapy, for a period of 2 months. Each patient was followed up fortnightly for the assessment of efficacy parameters using a pulmonary function test (PFT), clinical symptoms and emergency drug use, and safety was assessed by recording adverse drug reactions. RESULTS: Both Theophylline and doxofylline produced enhancements in PFT at different time intervals in both asthma and COPD patients. The maximum beneficial effects were seen at 6 weeks for asthma patients and at 8 weeks for COPD patients for both Theophylline and doxofylline. CONCLUSIONS: The comparative study showed that doxofylline was more effective as evidenced by improvement in PFT as well as clinical symptoms, and reduced incidence of adverse effects and emergency bronchodilator use.

Immunomodulation by theophylline in asthma. Demonstration by withdrawal of therapy.[Pubmed:7767539]

Am J Respir Crit Care Med. 1995 Jun;151(6):1907-14.

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)

Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages.[Pubmed:15337792]

J Exp Med. 2004 Sep 6;200(5):689-95.

Chronic obstructive pulmonary disease (COPD) is a common chronic inflammatory disease of the lungs with little or no response to glucocorticoids and a high level of oxidative stress. Histone deacetylase (HDAC) activity is reduced in cells of cigarette smokers, and low concentrations of Theophylline can increase HDAC activity. We measured the effect of Theophylline on HDAC activity and inflammatory gene expression in alveolar macrophages (AM) from patients with COPD. AM from normal smokers showed a decrease in HDAC activity compared with normal control subjects, and this was further reduced in COPD patients (51% decrease, P < 0.01). COPD AMs also showed increased basal release of IL-8 and TNF-alpha, which was poorly suppressed by dexamethasone. Theophylline induced a sixfold increase in HDAC activity in COPD AM lysates and significantly enhanced dexamethasone suppression of induced IL-8 release, an effect that was blocked by the HDAC inhibitor trichostatin A. Therefore, Theophylline might restore steroid responsiveness in COPD patients.

The formulation of a pressurized metered dose inhaler containing theophylline for inhalation.[Pubmed:25956075]

Eur J Pharm Sci. 2015 Aug 30;76:68-72.

BACKGROUND: Theophylline (TP) is a bronchodilator used orally to treat chronic obstructive pulmonary disease (COPD) that has been associated with multiple side effects, tempering its present use. This study aims to improve COPD treatment by creating a low-dose pressurized metered dose inhaler (pMDI) inhalable formulation of TP. METHODS: Aerosol performance was assessed using Andersen Cascade Impaction (ACI). Solubility of TP in HFA 134/ethanol mixture was measured and morphology of the particles analyzed with a scanning electron microscope (SEM). Calu-3 cell viability, epithelial cell transport and inflammatory-response assays were conducted to study the impact of the formulation on lung epithelial cells. RESULTS: The mass deposition profile of the formulation showed an emitted dose of 250.04+/-14.48mug per 5 actuations, achieving the designed nominal dose (50mug/dose). SEM showed that the emitted particles were hollow with spherical morphology. Approximately 98% of TP was transported across Calu-3 epithelial cells and the concentration of interleukin-8 secreted from Calu-3 cells following stimulation with tissue necrosis factor-alpha (TNF-alpha) resulted in significantly lower level of interleukin-8 released from the cells pre-treated with TP (1.92+/-0.77ng.ml(-1) TP treated vs. 8.83+/-2.05ng.ml(-1) TNF-alpha stimulated, respectively). CONCLUSIONS: The solution pMDI formulation of TP developed in present study was shown to be suitable for inhalation and demonstrated anti-inflammatory effects at low doses in Calu-3 cell model.

Theophylline antagonizes flurazepam-induced depression of cerebral cortical neurons.[Pubmed:497904]

Can J Physiol Pharmacol. 1979 Aug;57(8):917-20.

Intravenously administered Theophylline (50--100 mg/kg) antagonized the depressant actions of adenosine and flurazepam on rat cerebral cortical neurons. When assessed in conjunction with recent reports that Theophylline competes with diazepam for binding sites in brain tissue, this finding suggests that one action of the benzodiazepines may be exerted at a purinergic receptor associated with central neurons.

Theophylline accelerates human granulocyte apoptosis not via phosphodiesterase inhibition.[Pubmed:9312165]

J Clin Invest. 1997 Oct 1;100(7):1677-84.

Theophylline, in addition to its bronchodilator effect, is reported to have an antiinflammatory action that may account for its clinical effectiveness in the reduction of inflammatory cells in the airway. In bronchial asthma, such inflammatory cytokines as GM-CSF and IL-5 are upregulated and have been proposed to cause granulocyte infiltration (neutrophils and eosinophils) in the airway by inhibition of granulocyte apoptosis. We examined the abilities of Theophylline to counteract the prolongation of human granulocyte survival caused by cytokines. Theophylline was shown to shorten granulocyte survival in a dose-dependent manner. Upon incubation with a therapeutical concentration of Theophylline (0.1 mM; 18 microg/ml), percentages of GM-CSF (10 ng/ml)-induced delayed apoptosis increased from 18+/-2% to 38+/-3% (p < 0.02) in neutrophils and from 21+/-2% to 35+/-2% (p < 0.02; 24-h incubation) in eosinophils. The percentage of IL-5 (5 ng/ml)-induced delayed eosinophil apoptosis also increased from 22+/-4% to 33+/-2% (P < 0. 05). In contrast, cyclic AMP (cAMP)-increasing agents (3-isobutylmethylxanthine, dibutyryl cAMP, and rolipram) inhibited granulocyte apoptosis in the control and anti-Fas antibody-treated cells. In eosinophils, the expression of bcl-2 protein decreased after incubation with Theophylline. These findings suggest that Theophylline accelerates granulocyte apoptosis, which may play an essential role in inflammation, and controls granulocyte longevity regardless of the elevation of intracellular cAMP levels.

Recent advances in our understanding of the use of theophylline in the treatment of asthma.[Pubmed:10073321]

J Clin Pharmacol. 1999 Mar;39(3):237-40.

The use of Theophylline for the treatment of asthma for 45 of the past 50 years has been for its ability to dilate bronchi. The problem has been that at the most effective bronchodilating dose, toxicity was too close for comfort. In the past 5 years, there has been resurgence in Theophylline use at lower doses because of some well-documented anti-inflammatory and steroid sparing effects.

Theophylline is a nonselective phosphodiesterase (PDE) inhibitor, adenosine receptor blocker, and histone deacetylase (HDAC) activator.

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