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Theophylline (dimethyxanthine) has been used to treat airway diseases for over 80 years. 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 β2-agonists became more widely used. More recently it has been shown to have anti-inflammatory effects in...
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Theophylline (3-methyxanthine) has been used to treat airway diseases for over 70 years. 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 β2-agonists became more widely used. More recently it has been shown to have anti-inflammatory effects in...
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... However, there are some common side effects, like increased secretion of acid, nausea, and vomiting due to phosphodiesterase inhibition. Other side effects include cardiac arrhythmias and convulsions which occur at high concentrations of drug exposure [57]. Hence, other chemical drugs have also been adapted to treat the pulmonary associated inflammation. ...
Chronic inflammatory diseases are caused due to prolonged inflammation at a specific site of the body. Among other inflammatory diseases, bacterial meningitis, chronic obstructive pulmonary disease (COPD), atherosclerosis and inflammatory bowel diseases (IBD) are primarily focused on because of their adverse effects and fatality rates around the globe in recent times. In order to come up with novel strategies to eradicate these diseases, a clear understanding of the mechanisms of the diseases is needed. Similarly, detailed insight into the mechanisms of commercially available drugs and potent lead compounds from natural sources are also important to establish efficient therapeutic effects. Zebrafish is widely accepted as a model to study drug toxicity and the pharmacokinetic effects of the drug. Moreover, researchers use various inducers to trigger inf lammatory cascades and stimulate physiological changes in zebrafish. The effect of these inducers contrasts with the type of zebrafish used in the investigation. Hence, a thorough analysis is required to study the current advancements in the zebrafish model for chronic inflammatory disease suppression. This review presents the most common inflammatory diseases, commercially available drugs, novel therapeutics, and their mechanisms of action for disease suppression. The review also provides a detailed description of various zebrafish models for these diseases. Finally, the future prospects and challenges for the same are described, which can help the researchers understand the potency of the zebrafish model and its further exploration for disease attenuation.
... Various additional benefits can be obtained from developing CDDSs, as shown in Figure 1. Various types of medication require the utilization of CDDSs: for instance, drugs with a short half-life, such as furosemide [3], oxcarbazepine [4], and metoprolol [5], as well as medications with a narrow therapeutic window like theophylline monohydrate (THN) [6,7], Figure 1. Various types of medication require the utilization of CDDSs: for instance, drugs with a short half-life, such as furosemide [3], oxcarbazepine [4], and metoprolol [5], as well as medications with a narrow therapeutic window like theophylline monohydrate (THN) [6,7], lithium [8], and phenytoin [9]. ...
... Various types of medication require the utilization of CDDSs: for instance, drugs with a short half-life, such as furosemide [3], oxcarbazepine [4], and metoprolol [5], as well as medications with a narrow therapeutic window like theophylline monohydrate (THN) [6,7], Figure 1. Various types of medication require the utilization of CDDSs: for instance, drugs with a short half-life, such as furosemide [3], oxcarbazepine [4], and metoprolol [5], as well as medications with a narrow therapeutic window like theophylline monohydrate (THN) [6,7], lithium [8], and phenytoin [9]. However, the development of new CDDSs faces a range of challenges that must be addressed. ...
... THN was selected due to the reported challenges in maintaining controlled drug release functionality in some THN CR formulations [17,18]. Additionally, delivering THN in a CR system is preferred due to its rapid absorption, narrow therapeutic window (10 to 20 mg/mL), and short half-life (7 to 9 h) [6,7]. THN is mainly used for chronic obstructive pulmonary disease (COPD) and asthma [6,19]. ...
Background: Theophylline (THN), a bronchodilator with potential applications in emerging conditions like COVID-19, requires a controlled-release delivery system due to its narrow therapeutic range and short half-life. This need is particularly crucial as some existing formulations demonstrate impaired functionality. This study aims to develop a new 12-h controlled-release matrix system (CRMS) in the form of a capsule to optimize dosing intervals. Methods: CRMSs were developed using varying proportions of poloxamer 407 (P-407), stearyl alcohol (STA), and hydroxypropyl methylcellulose (HPMC) through the fusion technique. Their in vitro dissolution profiles were then compared with an FDA-approved THN drug across different pH media. The candidate formulation underwent characterization using X-ray diffraction, scanning electron microscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, and thermogravimetric analysis. Additionally, a comprehensive stability study was conducted. Results: In vitro studies showed that adjusting the concentrations of excipients effectively controlled drug release. Notably, the CRMS formulation 15 (CRMS-F15), which was composed of 30% P-407, 30% STA, and 10% HPMC, closely matched the 12 h controlled-release profile of an FDA-approved drug across various pH media. Characterization techniques verified the successful dispersion of the drug within the matrix. Furthermore, CRMS-F15 maintained a consistent controlled drug release and demonstrated stability under a range of storage conditions. Conclusions: The newly developed CRMS-F15 achieved a 12 h controlled release, comparable to its FDA-approved counterpart.
... Several recent studies have indicated new applications for THN, including posttuberculous lung disease [18] and COVID-19 [7]. However, THN has a well-established history of use in treating asthma [17] and chronic obstructive pulmonary disease [19,20]. THN, also known as 1,3-dimethylxanthine (Figure 1), is a white, odorless, and crystalline powder with a molecular weight of 180.17 g/mol and a melting point of 270-274 • C [7]. ...
... According to the Biopharmaceutical Classification System (BCS), THN is classified as a Class I compound, characterized by its high drug solubility and permeability [21,22]. The CR dosage form is recommended for THN due to its rapid absorption, narrow therapeutic window (5 to 20 mg/mL), and short half-life (3-8 h) [20,22]. ...
... Several recent studies have indicated new applications for THN, including post-tuberculous lung disease [18] and COVID-19 [7]. However, THN has a well-established history of use in treating asthma [17] and chronic obstructive pulmonary disease [19,20]. THN, also known as 1,3-dimethylxanthine (Figure 1), is a white, odorless, and crystalline powder with a molecular weight of 180.17 g/mol and a melting point of 270-274 °C [7]. ...
Background: Drug release from controlled release delivery systems is influenced by various factors, including the polymer’s grade and the drug’s hydration form. This study aimed to investigate the impact of these factors on the controlled release of theophylline (THN). This research compares the monohydrate form found in branded products with the anhydrous form in generic equivalents, each formulated with different polymer grades. Methods: Quality control assessment was conducted alongside in vitro evaluation, complemented by various analytical techniques such as X-ray diffraction (XRD) and scanning electron microscopy (SEM). Additionally, thermal analyses using differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) were employed. Results: Quality control assessments demonstrated that the generic tablets exhibited lower average weight and resistance force compared to the branded ones. In vitro tests revealed that generic tablets released contents within 120 min, compared to 720 min for the branded counterpart. Characterization using XRD and SEM identified disparities in crystallinity and particle distribution between the three samples. Additionally, the thermal analysis indicated consistent endothermic peaks across all samples, albeit with minor variations in heat flow and decomposition temperatures between the two products. Conclusions: This study demonstrated that variations in polymer grade and hydration form significantly impact THN release.
... Caffeine is most commonly known for its stimulating and awakening effects (Snel et al., 2004). Theobromine and theophylline are both known for acting as smooth muscle relaxants, and they have been used in the treatment of asthma (Simons et al., 1985;Smit, 2011;Zhang et al., 2010) and as a bronchodilator to treat asthma and chronic obstructive pulmonary disease (COPD) (Barnes, 2006(Barnes, , 2013Hayallah et al., 2011;Zhang et al., 2010), respectively. Less common and less well-known natural methylxanthines include paraxanthine (1,7-dimethylxanthine), 1-methylxanthine, 3-methylxanthine, and 7-methylxanthine. ...
1-Methylxanthine is a high-value derivative of caffeine of limited natural availability with many potential pharmaceutical applications. Unfortunately, production of 1-methylxanthine through purely chemical methods of synthesis are unfavorable due to lengthy chemical processes and the requirement of hazardous chemicals, ultimately resulting in low yields. Here, we describe a novel biosynthetic process for the production of 1-methylxanthine from theophylline using engineered Escherichia coli whole-cell biocatalysts and reaction optimization.When scaled-up to 1590 mL, the simple biocatalytic reaction produced approximately 1188 mg 1-methylxan-thine from 1444 mg theophylline, constituting gram-scale production of 1-methylxanthine in as little as 3 hours. Following HPLC purification and solvent evaporation, 1163 mg of dried 1-methylxanthine powder was collected, resulting in a 97.9 wt% product recovery at a purity of 97.8%. This is the first report of a biocatalytic process designed specifically for the production and purification of the high-value biochemical 1-methylxanthine from theophylline. This process is also the most robust methylxanthine N-demethylation process featuring engineered E. coli to date, capable of gram-scale production.
... Theophylline is an alkaloid compound that is effective for treating asthma and has been used for over 80 years [1]. Theophylline is consumed as a bronchodilator agent for asthma and obstructive chronic pulmonary disorders [2]. ...
Theophylline is a drug with a narrow therapeutic range. Electrochemical sensors are a potentially effective method for detecting theophylline concentration to prevent toxicity. In this work, a simple modification of a boron-doped diamond electrode using nickel nanoparticles was successfully performed for a theophylline electrochemical sensor. The modified electrode was characterized using a scanning electron microscope and X-ray photoelectron spectroscopy. Square wave voltammetry and cyclic voltammetry methods were used to study the electrochemical behavior of theophylline. The modified nickel nanoparticles on the boron-doped diamond electrode exhibited an electrochemically active surface area of 0.0081 cm2, which is larger than the unmodified boron-doped diamond’s area of 0.0011 cm2. This modified electrode demonstrated a low limit of detection of 2.79 µM within the linear concentration range from 30 to 100 µM. Moreover, the modified boron-doped diamond electrode also showed selective properties against D-glucose, ammonium sulfate, and urea. In the real sample analysis using artificial urine, the boron-doped diamond electrode with nickel nanoparticle modifications achieved a %recovery of 105.10%, with a good precision of less than 5%. The results of this work indicate that the developed method using nickel nanoparticles on a boron-doped diamond electrode is promising for the determination of theophylline.
... Syringate and theophylline have been reported to have therapeutic properties. Theophylline is a purine alkaloid which used to treat lung diseases like chronic obstructive pulmonary disease and asthma (Barnes 2013;Jilani et al. 2022). It acts as an anti-inflammatory agent, bronchodilator, and immunomodulatory agent (Vassallo and Lipsky 1998;Kanehara et al. 2008). ...
The current study aimed to evaluate and compare the effect of different concentrations (0.0–200.0 µM) of jasmonic acid (JA), methyl jasmonate (MeJA), and salicylic acid (SA) on suspension culture mass production and untargeted metabolic profiling of the medicinal plant Cymbopogon schoenanthus subsp. proximus. The addition of 50 µM MeJA improved the fresh weight of embryogenic tissue significantly. MeJA and SA did not affect tissue dry weight, whereas JA significantly decreased it. Based on 1H and 1H–13C NMR data and NMR databases, 50 compounds were identified. The addition of stress hormones resulted in the biosynthesis of novel metabolites like theophylline and syringate that were absent in control samples. In addition, significant variations in the concentrations of numerous compounds, including sugars, amino acids, organic acids, phenols, and alkaloids, were observed. The upregulation of trigonelline concentration was observed upon the addition of a higher concentration of MeJA (200 µM), whereas all tested concentrations of SA resulted in its upregulation. Addition of JA and SA causes significant changes in aminoacyl-tRNA biosynthesis pathway and amino acid metabolism pathways, such as alanine-aspartate and glutamate metabolism and arginine and proline metabolism. MeJA had significant impacts on glycolysis and starch-glucose metabolism pathways in addition to amino acids metabolism pathways. The present findings were successful in demonstrating a correlation and distinction between the effects of JA, MeJA, and SA, on the metabolome of Cymbopogon schoenanthus, a valuable medicinal plant. The identified metabolites and their associated pathways would be valuable in future biotechnology applications of the genus Cymbopogon.
... Syringate and theophylline have been reported to have therapeutic properties. Theophylline is a purine alkaloid which used to treat lung diseases like chronic obstructive pulmonary disease and asthma (Barnes 2013;Jilani et al. 2022). It acts as an anti-inflammatory agent, bronchodilator, and immunomodulatory agent (Vassallo and Lipsky 1998;Kanehara et al. 2008). ...
The current study aimed to evaluate and compare the effect of different concentrations (0.0–200.0 µM) of jasmonic acid (JA), methyl jasmonate (MeJA), and salicylic acid (SA) on suspension culture mass production and untargeted metabolic profiling of the medicinal plant Cymbopogon schoenanthus subsp. proximus. The addition of 50 µM MeJA improved the fresh weight of embryogenic tissue significantly. MeJA and SA did not affect tissue dry weight, whereas JA significantly decreased it. Based on ¹H and ¹H–¹³C NMR data and NMR databases, 50 compounds were identified. The addition of stress hormones resulted in the biosynthesis of novel metabolites like theophylline and syringate that were absent in control samples. In addition, significant variations in the concentrations of numerous compounds, including sugars, amino acids, organic acids, phenols, and alkaloids, were observed. The upregulation of trigonelline concentration was observed upon the addition of a higher concentration of MeJA (200 µM), whereas all tested concentrations of SA resulted in its upregulation. Addition of JA and SA causes significant changes in aminoacyl-tRNA biosynthesis pathway and amino acid metabolism pathways, such as alanine-aspartate and glutamate metabolism and arginine and proline metabolism. MeJA had significant impacts on glycolysis and starch-glucose metabolism pathways in addition to amino acids metabolism pathways. The present findings were successful in demonstrating a correlation and distinction between the effects of JA, MeJA, and SA, on the metabolome of Cymbopogon schoenanthus, a valuable medicinal plant. The identified metabolites and their associated pathways would be valuable in future biotechnology applications of the genus Cymbopogon.
... It has been well established that the systemic administration of methylxanthines profoundly affects hemodynamic parameters, such as blood pressure and heart rate, and stimulates the respiratory and central nervous systems [74,75]. Methylxanthines exert their effects by at least five primary mechanisms: 1) the nonselective antagonism of ARs (all subtypes) [76], 2) the competitive inhibition of phosphodiesterase (PDE isoenzymes III and IV) [77], 3) the modulation of GABA A receptors [78], 4) the mobilization of intracellular calcium [79], and 5) the activation of histone deacetylase (isoenzyme type II) [80]. However, due to the very similar affinities of caffeine and adenosine to binding A1 and A2A receptors, it has been shown that after the moderate consumption of methylxanthine-containing beverages, such as coffee, their effects are primarily due to the antagonism of ARs [81,82]. ...
Adenosine is an endogenous nucleoside that regulates many physiological and pathological processes. It is derived from either the intracellular or extracellular dephosphorylation of adenosine triphosphate and interacts with cell-surface G-protein-coupled receptors. Adenosine plays a substantial role in protecting against cell damage in areas of increased tissue metabolism and preventing organ dysfunction in pathological states. Targeting adenosine metabolism and receptor signaling may be an effective therapeutic approach for human diseases, including cardiovascular and central nervous system disorders, rheumatoid arthritis, asthma, renal diseases, and cancer. Several lines of evidence have shown that many drugs exert their beneficial effects by modulating adenosine signaling pathways but this knowledge urgently needs to be summarized, and most importantly, actualized. The present review collects pharmaceuticals and pharmacological or diagnostic tools that target adenosine signaling in their primary or secondary mode of action. We overviewed FDA-approved drugs as well as those currently being studied in clinical trials. Among them are already used in clinic A2A adenosine receptor modulators like istradefylline or regadenoson, but also plenty of anti-platelet, anti-inflammatory, or immunosuppressive, and anti-cancer drugs. On the other hand, we investigated dozens of specific adenosine pathway regulators that are tested in clinical trials to treat human infectious and noninfectious diseases. In conclusion, targeting purinergic signaling represents a great therapeutic challenge. The actual knowledge of the involvement of adenosinergic signaling as part of the mechanism of action of old drugs has open a path not only for drug-repurposing but also for new therapeutic strategies.
... Theophylline (1,3-dimethyl-7H-purine-2,6-dione) (TP) is a dimethylxanthine derived from the xanthine purine base of alkaloid, which occurs naturally in most kinds of teas (jasmine tea, black tea, oolong tea, etc.) and cocoa beans in trace amounts [1][2][3]. TP is an important bioactive component of tea, which has various bioactivities at low doses [4]. TP can relax the airway smooth muscle mainly through the inhibition of phosphodiesterase (PDE)3 activity [1]. ...
... TP is an important bioactive component of tea, which has various bioactivities at low doses [4]. TP can relax the airway smooth muscle mainly through the inhibition of phosphodiesterase (PDE)3 activity [1]. It is widely used to treat airway obstruction caused by clinical conditions such as asthma, infant apnea, chronic bronchitis, emphysema, and chronic obstructive pulmonary disease [5][6][7]. ...
A core-shell-derived structural magnetic zeolite imidazolate framework-67 (Fe3O4-COOH@ZIF-67) nanocomposite was fabricated through a single-step coating of zeolite imidazolate framework-67 on glutaric anhydride-functionalized Fe3O4 nanosphere for the magnetic solid-phase extraction (MSPE) of theophylline (TP). The Fe3O4-COOH@ZIF-67 nanocomposite was characterized through scanning electron microscopy, transmission electron microscopy, energy dispersive X-ray spectrometry, Fourier transform infrared spectroscopy, Zeta potential analysis, X-ray diffraction, Brunauer-Emmett-Teller, and vibrating sample magnetometer. The material has a high specific surface area and good magnetism, which maintains the regular dodecahedron structure of ZIF-67 without being destroyed by the addition of Fe3O4-COOH nanospheres. The Fe3O4-COOH@ZIF-67 can rapidly adsorb TP mainly through the strong coordination interaction between undercoordinated Co2+ on ZIF-67 and -NH from imidazole of TP. The adsorption and desorption conditions, such as the amount of adsorbent, adsorption time, pH value, and elution solvent, were optimized. The kinetics of TP adsorption on Fe3O4-COOH@ZIF-67 was found to follow pseudo-second-order kinetics. The Langmuir model fits the adsorption data well and the maximum adsorption capacity is 1764 mg/g. Finally, the developed MSPE-HPLC method was applied in the enrichment and analysis of TP in four tea samples and rabbit plasma. TP was not detected in oolong tea and rabbit plasma, and its contents in jasmine tea, black tea, and green tea are 5.80, 4.31, and 1.53 μg/g, respectively. The recoveries of spiked samples are between 74.41% and 86.07% with RSD in the range of 0.81-3.83%. The adsorption performance of Fe3O4-COOH@ZIF-67 nanocomposite was nearly unchanged after being stored at room temperature for at least 80 days and two consecutive adsorption-desorption cycles. The results demonstrate that Fe3O4-COOH@ZIF-67 nanocomposite is a promising magnetic adsorbent for the preconcentration of TP in complex samples.
... It also has neuroprotective effects and can be used to treat neurodegenerative diseases [102]. Theophylline, a type of methylxanthine, possesses anti-inflammatory effects on chronic obstructive pulmonary disease and asthma [103,104]. Moreover, theobromine, another type of methylxanthine, has an obvious anticough effect without side effects [105], and paraxanthine can be used in the treatment of Parkinson's disease [106]. ...
Caffeine is a metabolite derived from purine nucleotides, typically accounting for 2-5% of the dry weight of tea and 1-2% of the dry weight of coffee. In the tea and coffee plants, the main synthesis pathway of caffeine is a four-step sequence consisting of three methylation reactions and one nucleosidase reaction using xanthine as a precursor. In bacteria, caffeine degradation occurs mainly through the pathways of N-demethylation and C-8 oxidation. However, a study fully and systematically summarizing the metabolism and application of caffeine in microorganisms has not been established elsewhere. In the present study, we provide a review of the biosynthesis, microbial degradation, gene expression, and application of caffeine microbial degradation. The present review aims to further elaborate the mechanism of caffeine metabolism by microorganisms and explore the development prospects in this field.
