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Antiasthma Agents during Pregnancy
Published in “Bert” Bertis Britt Little, Drugs and Pregnancy, 2022
A xanthine derivative, theophylline, has potent diuretic effects and is commonly used for bronchodilation actions. It is a competitive inhibitor of phosphodiesterase, which inactivates cAMP (Feldman and McFadden, 1977). Increased intracellular cAMP levels stimulates bronchodilation. Theophylline salts were previously the first line of therapy for asthma control during pregnancy. The frequency of congenital anomalies was not increased among 606 infants whose mothers used theophylline during the first trimester. Similarly, birth defects were not increased in frequency in 1294 infants whose mothers used the drug any time during pregnancy (Heinonen et al., 1977; Schatz et al., 1997; Stenius-Aarniala et al., 1995).
Chocolate Folklore
Published in Linda K. Fuller, Chocolate Fads, Folklore, & Fantasies, 2020
About a dozen years ago a concern arose about xanthine alkaloids in chocolate, coffee, tea, and cola drinks and their possible effects on benign breast disease. Yet the early studies were criticized for inadequate controls, and later ones have shown that comparisons of before-after mammograms offered little support for a correlation.
Cerebral energy metabolism and blood flow: useful tools for the understanding of the behavioral effects of caffeine
Published in B.S. Gupta, Uma Gupta, Caffeine and Behavior, 2020
In most situations, cerebral blood flow and glucose utilization are closely coupled in all cerebral regions, so that modifications in cerebral activity elicit parallel changes in cerebral glucose utilization and blood flow.5,8,9,62 In general, changes in cerebral blood flow are the consequence of variations in cerebral energy metabolism.7,10,11 Contrary to the majority of pharmacological agents to which man is frequently exposed, and as shown in Figure 3.5, caffeine has the property to induce cerebral hypoperfusion accompanied by a simultaneous increase in glucose utilization15,19,52; in other words, caffeine resets the level of coupling between cerebral blood flow and energy metabolism. Methylxanthines thus seem to modify the regulating mechanism between cerebral blood flow and cerebral metabolism. Although this mechanism is not yet fully understood, adenosine, with which methylxanthines compete, is known to be one of the modulators of the regulation of the relationship of blood flow to metabolism in the central nervous system.5,6,62 Indeed, theobromine, a weaker adenosine antagonist than caffeine or theophylline, has only minor effects on cerebral blood flow and metabolism, while propento-phylline, an adenosine uptake blocker, induces the reverse effect, i.e., an increase in cerebral blood flow and a decrease in glucose utilization. Thus, several xanthine derivatives can reset the relationship between metabolism and blood flow in the brain.63
Evaluating the therapeutic effect and toxicity of theophylline in infertile men with asthenoteratozoospermia: a double-blind, randomized clinical trial study
Published in Drug and Chemical Toxicology, 2022
Atena Sadat Azimi, Malek Soleimani Mehranjani, Seyed Mohammad Ali Shariatzadeh, Alireza Noshad Kamran, Ali Asghar Ghafarizadeh
In addition to inhibiting phosphodiesterases, theophylline also inhibits the sperm alkaline phosphatase (ALP). This inhibitory effect of theophylline is much stronger than the other methyl-xanthines such as caffeine and pentoxifylline (Glogowski et al.2002). Dogan et al. (2009) indicated a negative correlation between the level of seminal plasma ALP and the sperm DNA fragmentation. Moreover, within the therapeutic dose, theophylline inhibits Bcl-2 expression and causes the downregulation of BCL-2 gene (Bernges and Zeller 1996). This could all explain the increase found in DNA fragmentation following theophylline treatment and the toxicity of it. The exact mechanism of theophylline, however, remains unclear and further studies are needed to evaluate the toxic effects of theophylline on DNA of sperms in asthenoteratozoospermic men.
Recent developments in predicting CYP-independent metabolism
Published in Drug Metabolism Reviews, 2021
Nikhilesh V. Dhuria, Bianka Haro, Amit Kapadia, Khadjia A. Lobo, Bernice Matusow, Mary A. Schleiff, Christina Tantoy, Jasleen K. Sodhi
Xanthine oxidase (XO) is a molybdenum-containing cytosolic enzyme that is structurally related to AO, requires the same cofactors, and has a similar mechanism of action (Alfaro and Jones 2008), although they differ in terms of their substrate specificities (Garattini and Terao 2012). XO is involved in the metabolism of purines, oxidizing hypoxanthine to xanthine, and xanthine to uric acid (Hille and Nishino 1995; Battelli et al. 2016). XO is recognized to play an important role in xenobiotic metabolism, in particular for certain anticancer, immunosuppressive, antimicrobial, antiviral, or vasodilator drugs (Battelli et al. 2016). The physiological function of XO is also well-established, as XO is linked with various pathological disorders such as gout, cardiovascular disease and cancer (Higgins et al. 2012; Bredemeier et al. 2018; Xu et al. 2019), and of note the XO inhibitor allopurinol has been used clinically for treatment of hyperuricemia (which often leads to gout) for over 50 years (Klinenberg et al. 1965). Recently, a number of investigators have taken in vitro, in vivo, and in silico approaches toward the discovery of novel XO inhibitors with desirable properties, such as improved potency and selectivity compared with allopurinol (Borges et al. 2002; Malik et al. 2017; Sato et al. 2018; Luna et al. 2019; Mohos et al. 2019; Zhang et al. 2019; Nawaz et al. 2020).
The protective effect of doxofylline against lipopolysaccharides (LPS)-induced activation of NLRP3 inflammasome is mediated by SIRT1 in human pulmonary bronchial epithelial cells
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2020
Peng Jiao, Weiming Li, Lin Shen, Yan Li, Lili Yu, Zhaohui Liu
Xanthine derivatives such as theophylline have long been used to treat lung diseases, but many of them have demonstrated limited effect as well as various side effects. Doxofylline is the most recently modified theophylline-based compound and has been approved to treat lung diseases such as COPD and asthma [10]. The chemical name of doxofylline is 7-(1,3 dioxolar-2-ylmethyl)-theophylline. Compared with theophylline, doxofylline has a dioxalane group at position 7. Doxofylline has improved efficacy as compared to theophylline but shows fewer side effects and is viewed as a replacement for theophylline [11]. Doxofylline possesses potent anti-inflammatory and bronchodilatory activities, and it acts as a non-selective phosphodiesterase (PDE) inhibitor. However, whether doxofylline has a protective effect against LPS exposure in bronchial epithelial cells and the underlying mechanisms are still unknown. In this study, we explored its protective mechanism against LPS-induced inflammation in cultured bronchial epithelial cells. Our findings reveal that doxofylline mitigated LPS-induced bronchial epithelial cells inflammation by suppressing the activation of the NLRP3 inflammasome.