-
International Journal of Chronic... 2017Doxofylline, which differs from theophylline in containing the dioxalane group at position 7, has comparable efficacy to theophylline in the treatment of respiratory... (Review)
Review
Doxofylline, which differs from theophylline in containing the dioxalane group at position 7, has comparable efficacy to theophylline in the treatment of respiratory diseases, but with an improved tolerability profile and a favorable risk-to-benefit ratio. Furthermore, it does not have significant drug-drug interactions as exhibited with theophylline, which make using theophylline more challenging, especially in elderly patients with co-morbidities receiving multiple classes of drug. It is now clear that doxofylline also possesses a distinct pharmacological profile from theophylline (no significant effect on any of the known phosphodiesterase isoforms, no significant adenosine receptor antagonism, no direct effect on histone deacetylases, interaction with β-adrenoceptors) and therefore, should not be considered as just a modified theophylline. Randomized clinical trials of doxofylline to investigate the use of this drug to reduce exacerbations and hospitalizations due to asthma or COPD as an alternative to expensive biologics, and certainly as an alternative to theophylline are to be encouraged.
Topics: Animals; Asthma; Bronchodilator Agents; Disease Progression; Drug Interactions; Hospitalization; Humans; Lung; Pulmonary Disease, Chronic Obstructive; Risk Factors; Theophylline; Treatment Outcome
PubMed: 29255355
DOI: 10.2147/COPD.S150887 -
Respiratory Medicine Apr 2020Theophylline is still one of the most widely prescribed drugs for the treatment of asthma and COPD in developing countries because the majority of asthma and COPD... (Review)
Review
Theophylline is still one of the most widely prescribed drugs for the treatment of asthma and COPD in developing countries because the majority of asthma and COPD medicines are largely unavailable and also because it is a cheap option. In any case, its anti-inflammatory effects and capacity to reverse corticosteroid resistance deserve consideration, but it can induce numerous side effects and drug-drug interactions and frequently requires measurement of drug levels in plasma. In order to overcome the problems posed by theophylline, other xanthines have been developed. Doxofylline is a newer generation xanthine with both bronchodilating and anti-inflammatory activities and for this reason it has been called "novofylline". It differs substantially from theophylline at the pharmacological level. Clinical studies have shown substantial differences between doxofylline and theophylline. In particular, efficacy/safety profile of doxofylline is better than that of theophylline.
Topics: Anti-Inflammatory Agents; Asthma; Bronchodilator Agents; Drug Costs; Economics, Pharmaceutical; Female; Humans; Male; Pulmonary Disease, Chronic Obstructive; Theophylline; Treatment Outcome
PubMed: 32094104
DOI: 10.1016/j.rmed.2020.105904 -
Drug Design, Development and Therapy 2018Theophylline 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... (Meta-Analysis)
Meta-Analysis Review
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 (=0.01) and overall duration of stay (=0.002), but beta-2 agonists were superior to theophylline at improving forced expiratory volume in one second (FEV1) (=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: <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.
Topics: Acute Disease; Administration, Intravenous; Anti-Asthmatic Agents; Asthma; Bronchodilator Agents; Humans; Theophylline
PubMed: 29391776
DOI: 10.2147/DDDT.S156509 -
Indian Journal of Pharmacology 2015A 53-year-old woman visited her physician complaining of acute breathlessness and productive cough. Her medications included budesonide and formoterol for asthma,...
A 53-year-old woman visited her physician complaining of acute breathlessness and productive cough. Her medications included budesonide and formoterol for asthma, fixed-dose combination aspirin 150 mg + clopidogrel 75 mg + atorvastatin 20 mg for ischemic heart disease. History revealed that she had allergic rhinitis and was hypersensitive to penicillins. The patient was prescribed acebrophylline (ABP). Six hours after ABP therapy she presented with generalized urticarial lesions, swelling of hands, feet, lips and face, suggestive of angioedema. ABP was stopped immediately, and the patient was treated symptomatically. This case was categorized as probable as per standard causality assessment scale.
Topics: Ambroxol; Angioedema; Asthma; Bronchitis; Bronchodilator Agents; Female; Humans; Middle Aged; Theophylline; Treatment Outcome
PubMed: 25878387
DOI: 10.4103/0253-7613.153435 -
The European Respiratory Journal Mar 1995
Topics: Adjuvants, Immunologic; Animals; Anti-Inflammatory Agents, Non-Steroidal; Asthma; Endothelium, Vascular; Guinea Pigs; Humans; Phosphodiesterase Inhibitors; T-Lymphocytes; Theophylline
PubMed: 7789475
DOI: 10.1183/09031936.95.08030347 -
Microbiology Spectrum Feb 2023Riboswitches are promising regulatory tools in synthetic biology. To date, 25 theophylline riboswitches have been developed for regulation of gene expression in...
Riboswitches are promising regulatory tools in synthetic biology. To date, 25 theophylline riboswitches have been developed for regulation of gene expression in bacteria. However, no one has systematically evaluated their regulatory effects. To promote efficient selection and application of theophylline riboswitches, we examined 25 theophylline riboswitches in Escherichia coli MG1655 and found that they varied widely in terms of activation/repression ratios and expression levels in the absence of theophylline. Of the 20 riboswitches that activate gene expression, only one exhibited a high activation ratio (63.6-fold) and low expression level without theophylline. Furthermore, none of the five riboswitches that repress gene expression were more than 2.0-fold efficient. To obtain an effective repression system, we rationally designed a novel theophylline riboswitch to control a downstream gene or genes by premature transcription termination. This riboswitch allowed theophylline-dependent downregulation of the TurboRFP reporter in a dose- and time-dependent manner. Its performance profile exceeded those of previously described repressive theophylline riboswitches. We then introduced as the second part a RepA tag (protein degradation tag) coding sequence fused at the 5'-terminal end of the gene, which further reduced protein level, while not reducing the repressive effect of the riboswitch. By combining two tandem theophylline riboswitches with a RepA tag, we constructed a regulatory cassette that represses the expression of the gene(s) of interest at both the transcriptional and posttranslational levels. This regulatory cassette can be used to repress the expression of any gene of interest and represents a crucial step toward harnessing theophylline riboswitches and expanding the synthetic biology toolbox. A variety of gene expression regulation tools with significant regulatory effects are essential for the construction of complex gene circuits in synthetic biology. Riboswitches have received wide attention due to their unique biochemical, structural, and genetic properties. Here, we have not only systematically and precisely characterized the regulatory properties of previously developed theophylline riboswitches but also engineered a novel repressive theophylline riboswitch acting at the transcriptional level. By introducing coding sequences of a tandem riboswitch and a RepA protein degradation tag at the 5' end of the reporter gene, we successfully constructed a simple and effective regulatory cassette for gene regulation. Our work provides useful biological components for the construction of synthetic biology gene circuits.
Topics: Riboswitch; Theophylline; Genes, Reporter; Gene Expression Regulation; Transcription, Genetic; Escherichia coli
PubMed: 36688639
DOI: 10.1128/spectrum.02752-22 -
PloS One 2022Tunable genetic controllers play a critical role in the engineering of biological systems that respond to environmental and cellular signals. RNA devices, a class of...
Tunable genetic controllers play a critical role in the engineering of biological systems that respond to environmental and cellular signals. RNA devices, a class of engineered RNA-based controllers, enable tunable gene expression control of target genes in response to molecular effectors. RNA devices have been demonstrated in a number of systems showing proof-of-concept of applying ligand-responsive control over therapeutic activities, including regulation of cell fate decisions such as T cell proliferation and apoptosis. Here, we describe the application of a theophylline-responsive RNA device in a muscle progenitor cell system to control myogenic differentiation. Ribozyme-based RNA switches responsive to theophylline control fluorescent reporter expression in C2C12 myoblasts in a ligand dependent manner. HRAS and JAK1, both anti-differentiation proteins, were incorporated into RNA devices. Finally, we demonstrate that the regulation of HRAS expression via theophylline-responsive RNA devices results in the modulation of myoblast differentiation in a theophylline-dependent manner. Our work highlights the potential for RNA devices to exert drug-responsive, tunable control over cell fate decisions with applications in stem cell therapy and basic stem cell biology research.
Topics: Cell Differentiation; Ligands; Muscle Development; Myoblasts; RNA; RNA, Catalytic; Theophylline
PubMed: 36166456
DOI: 10.1371/journal.pone.0275298 -
Thorax Jul 1985Total plasma and mixed stimulated saliva theophylline concentrations (by high performance liquid chromatography) and free plasma theophylline concentrations (by...
Total plasma and mixed stimulated saliva theophylline concentrations (by high performance liquid chromatography) and free plasma theophylline concentrations (by equilibrium dialysis) were measured in simultaneously collected samples from 32 outpatients receiving chronic oral theophylline treatment, who had received the drug at least two hours before sampling. There was a close relationship between saliva and total plasma theophylline concentration and between total saliva and free plasma concentration. The mean saliva to total plasma drug concentration ratio was 0.69 (SE 0.09) and the mean difference between paired saliva and free plasma concentration was 0.65 (0.17) microgram/ml. It is concluded that stimulated mixed saliva provides a simple, non-invasive method of assessing total (and free) plasma theophylline concentrations during chronic oral treatment. The therapeutic range for saliva, corresponding to the generally accepted total plasma concentration range (10-20 micrograms/ml), is approximately 7-14 micrograms/ml.
Topics: Adult; Aged; Chromatography, High Pressure Liquid; Female; Humans; Lung Diseases, Obstructive; Male; Middle Aged; Saliva; Theophylline
PubMed: 4035619
DOI: 10.1136/thx.40.7.526 -
The European Respiratory Journal Jun 1995Theophylline has been in clinical use for the treatment of bronchial asthma and other respiratory diseases for well over 50 yrs. Over this time, a considerable body of... (Review)
Review
Theophylline has been in clinical use for the treatment of bronchial asthma and other respiratory diseases for well over 50 yrs. Over this time, a considerable body of evidence has accumulated to show that this drug has a wide range of pharmacological actions, in addition to the well-recognized action on airway smooth muscle function. Current evidence suggests that part of the therapeutic value of theophylline in the treatment of asthma is by virtue of an anti-inflammatory or immunomodulatory effect, although the actual mechanism of action remains unclear. It has been proposed that the observed anti-inflammatory effects of theophylline could be attributed to phosphodiesterase (PDE) inhibition, and recently the type III and IV isoenzymes have been characterized in a number of inflammatory cells. This article reviews the evidence that theophylline and the newer more selective type IV PDE isoenzyme inhibitors can inhibit the activation of inflammatory cell types, such as T-lymphocytes, eosinophils, mast cells and macrophages, in vitro. The evidence supporting the ability of theophylline and selective PDE IV isoenzyme inhibitors to modify allergic inflammation both in animal models and clinical asthma is also discussed. We conclude that theophylline possesses important anti-inflammatory and immunomodulatory activity and that, in light of this evidence, it is timely to reconsider the place of theophylline in the treatment of asthma.
Topics: Animals; Anti-Inflammatory Agents; Asthma; Guinea Pigs; Humans; Phosphodiesterase Inhibitors; Theophylline
PubMed: 7589387
DOI: No ID Found -
Proceedings of the National Academy of... Nov 2022There is growing interest in therapeutic intervention that targets disease-relevant RNAs using small molecules. While there have been some successes in RNA-targeted...
There is growing interest in therapeutic intervention that targets disease-relevant RNAs using small molecules. While there have been some successes in RNA-targeted small-molecule discovery, a deeper understanding of structure-activity relationships in pursuing these targets has remained elusive. One of the best-studied tertiary-structured RNAs is the theophylline aptamer, which binds theophylline with high affinity and selectivity. Although not a drug target, this aptamer has had many applications, especially pertaining to genetic control circuits. Heretofore, no compound has been shown to bind the theophylline aptamer with greater affinity than theophylline itself. However, by carrying out a high-throughput screen of low-molecular-weight compounds, several unique hits were identified that are chemically distinct from theophylline and bind with up to 340-fold greater affinity. Multiple atomic-resolution X-ray crystal structures were determined to investigate the binding mode of theophylline and four of the best hits. These structures reveal both the rigidity of the theophylline aptamer binding pocket and the opportunity for other ligands to bind more tightly in this pocket by forming additional hydrogen-bonding interactions. These results give encouragement that the same approaches to drug discovery that have been applied so successfully to proteins can also be applied to RNAs.
Topics: RNA; Theophylline; Aptamers, Nucleotide; Ligands; Structure-Activity Relationship
PubMed: 36413497
DOI: 10.1073/pnas.2213117119