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Saiphoklang N, Panichaporn S, Siriyothipun T, Ruchiwit P. Effects of Oral Doxofylline and Procaterol on Chronic Obstructive Pulmonary Disease: A Randomized Crossover Study. Med Sci (Basel) 2025; 13:49. [PMID: 40407544 PMCID: PMC12101363 DOI: 10.3390/medsci13020049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2025] [Revised: 04/20/2025] [Accepted: 04/24/2025] [Indexed: 05/26/2025] Open
Abstract
Background: Oral bronchodilators may serve as an adjunctive therapy in patients with chronic obstructive pulmonary disease (COPD). This study aimed to evaluate the effects of oral doxofylline and oral procaterol on lung function and clinical symptoms in COPD patients. Methods: A crossover randomized controlled trial was conducted in patients with clinically stable COPD. Participants first received either doxofylline or procaterol for 4 weeks, followed by a 1-week washout period. Assessments included the modified Medical Research Council (mMRC) dyspnea scale, COPD assessment test (CAT) scores, and 6-minute walking distance (6MWD). Pulmonary function was evaluated using spirometry with bronchodilator (BD) testing and all adverse events were recorded. Results: Twenty patients were randomly assigned to begin treatment with either doxofylline or procaterol. Their mean age was 71.7 ± 9.4 years. After four weeks of treatment, the doxofylline group showed significantly greater improvement in pulmonary function parameters (post-BD peak expiratory flow and post-BD forced expiratory flow 25-75) compared to the procaterol group. However, there were no significant differences in mMRC scores, CAT scores, or 6MWD between the two groups. More neurological adverse events were observed in the doxofylline group compared to the procaterol group (35% vs. 5%, p = 0.044). Conclusions: Doxofylline improved pulmonary function in COPD patients but did not provide superior functional performance compared to procaterol. Neurological adverse events were more frequently associated with doxofylline. Doxofylline may serve as an adjunctive therapy to enhance pulmonary function in COPD patients, but caution is advised due to its potential side effects.
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Affiliation(s)
- Narongkorn Saiphoklang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Faculty of Medicine, Thammasat University, Pathum Thani 12120, Thailand; (S.P.); (T.S.); (P.R.)
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Gao F, Li J, Hou Y, Sun S, Chen Y, Cao F, Xu H, Li J. Efficacy and safety profile of doxofylline in asthma: a meta-analysis. J Asthma 2025; 62:205-215. [PMID: 39264111 DOI: 10.1080/02770903.2024.2404192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 09/10/2024] [Indexed: 09/13/2024]
Abstract
OBJECTIVE This work aims to explore the effectiveness and safety of doxofylline in asthma treatment. DATA SOURCES Relevant studies published before March 2023 were retrieved from EMBASE, Cochrane Library, PubMed, and Web of Science databases. STUDY SELECTIONS Risk of Bias tool (RoB 2) was applied to determine the quality of randomized controlled trials (RCTs). Relative risks (RR, 95% confidence intervals [CI]) and weighted mean differences (WMD, 95% CI) were calculated for dichotomous and continuous outcomes, respectively, under fixed or random-effects models. RESULTS A total of eight clinical trials comprising 1627 patients were analyzed. The meta-analysis revealed no notable change in forced expiratory volume in 1 s (FEV1) (WMD = 0.48; 95% CI: -2.09 to 3.05), the use of albuterol as a rescue medication (WMD = -0.02; 95% CI: -0.57 to 0.52), forced vital capacity (FVC) (WMD = 0.19; 95% CI: -0.28 to 0.67) and FEV1 predicted value (WMD = 1.53; 95%CI: -0.88 to 3.94) between doxofylline and control groups. However, doxofylline treatment significantly reduced adverse reactions (RR = 0.71; 95% CI: 0.60 to 0.84) and decreased the incidence of asthma events (WMD = -0.18; 95% CI: -0.33 to 0.03). Subgroup analysis results indicated that the improvement in FEV1 with doxofylline combined with budesonide was superior to that of budesonide combined with montelukast or tiotropium but inferior to that of budesonide plus formoterol combination. CONCLUSION Doxofylline treatment significantly reduces the risk of asthma events and adverse events (AEs), demonstrating good safety and longer-term benefits.
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Affiliation(s)
- Fa Gao
- College of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Jian Li
- College of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Yulong Hou
- College of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Shuxin Sun
- College of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Yiyuan Chen
- College of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Fang Cao
- School of Basic Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Hang Xu
- College of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Jing Li
- Pediatrics, Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, Jilin, China
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Yu D, Liu M, Tang W. Doxophylline With Paroxysmal Supraventricular Tachycardia: A Case Report. CLINICAL MEDICINE INSIGHTS-CASE REPORTS 2024; 17:11795476241266395. [PMID: 39282243 PMCID: PMC11402082 DOI: 10.1177/11795476241266395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 06/14/2024] [Indexed: 09/18/2024]
Abstract
Purpose We report a case of a patient experiencing paroxysmal supraventricular tachycardia after infusing doxophylline. Methods Clinical evaluations and the electrocardiogram were performed by specialists. Findings Our patient felt palpitations and chest distress after intravenous Doxophylline. The electrocardiogram showed paroxysmal supraventricular tachycardia. There was no evidence to prove that there was any problem with his heart, liver, and kidney. According to the Naranjo Adverse Drug Reaction probability scale, paroxysmal supraventricular tachycardia has a probable relationship with Doxophylline. Implications The paroxysmal supraventricular tachycardia is a rare but reasonable adverse reaction of Doxophylline, which should be paid more attention.
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Affiliation(s)
- Dandan Yu
- Department of Neurology, Dalian University Affiliated Xinhua Hospital, Dalian, Liaoning, China
| | - Min Liu
- Department of Neurology, Dalian University Affiliated Xinhua Hospital, Dalian, Liaoning, China
| | - Wei Tang
- Department of Neurology, Dalian University Affiliated Xinhua Hospital, Dalian, Liaoning, China
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Scurek M, Brat K. A narrative review of theophylline: is there still a place for an old friend? J Thorac Dis 2024; 16:3450-3460. [PMID: 38883616 PMCID: PMC11170423 DOI: 10.21037/jtd-23-1781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Accepted: 05/17/2024] [Indexed: 06/18/2024]
Abstract
Background and Objective Theophylline has been used for decades in human medicine for its psychostimulant, anti-inflammatory, and bronchodilator effects. Historically, in pulmonary medicine, theophylline has been used in the treatment of obstructive pulmonary diseases such as bronchial asthma (BA) or chronic obstructive pulmonary disease (COPD). This review aims to determine whether theophylline still has its place in the therapy of obstructive pulmonary diseases or whether we can even extend its use to other diagnoses such as atropine-resistant cardiac arrests, apnea of prematurity, or others. Moreover, we also aim to determine if there is a rationale for using low-dose theophylline due to its immunomodulatory and anti-inflammatory effect, or if the future of methylxanthines lies in newly synthesized derivates of theophylline such as bamifylline, or doxofylline. Methods The narrative review is based on a literature search of the articles indexed in the PubMed database in 2023. We searched the database since the year 2009 using the MeSH terms "theophylline", "aminophylline", and "methylxanthines" and we included original articles in the English language. Key Content and Findings Theophylline has a number of adverse drug reactions (ADRs), the most serious of which is its effect on the cardiovascular system. It can cause severe arrhythmias or even cardiac arrest when overdosed. On the other hand, there is still a substantial amount of its applications in current clinical practice. Conclusions There is considerable controversy associated with its use in current medicine, which can be attributed both to its narrow therapeutic range and its mentioned cardiotoxic effect. Herein, we summarize the current state-of-art of theophylline and its use in human medicine.
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Affiliation(s)
- Martin Scurek
- Department of Respiratory Diseases, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czechia
| | - Kristian Brat
- Department of Respiratory Diseases, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czechia
- International Clinical Research Center, St. Anne's University Hospital, Brno, Czechia
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Zhao Z, Song F, Kimura S, Onodera T, Uchida T, Toko K. Assessment of Bitterness in Non-Charged Pharmaceuticals with a Taste Sensor: A Study on Substances with Xanthine Scaffold and Allopurinol. Molecules 2024; 29:2452. [PMID: 38893328 PMCID: PMC11173402 DOI: 10.3390/molecules29112452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 05/16/2024] [Accepted: 05/17/2024] [Indexed: 06/21/2024] Open
Abstract
Taste sensors with an allostery approach have been studied to detect non-charged bitter substances, such as xanthine derivatives, used in foods (e.g., caffeine) or pharmaceuticals (e.g., etofylline). In this study, the authors modified a taste sensor with 3-bromo-2,6-dihydroxybenzoic acid and used it in conjunction with sensory tests to assess the bitterness of non-charged pharmaceuticals with xanthine scaffolds (i.e., acefylline and doxofylline), as well as allopurinol, an analogue of hypoxanthine. The results show that the sensor was able to differentiate between different levels of sample bitterness. For instance, when assessing a 30 mM sample solution, the sensor response to acefylline was 34.24 mV, which corresponded to the highest level of bitterness (τ = 3.50), while the response to allopurinol was lowest at 2.72 mV, corresponding to relatively weaker bitterness (τ = 0.50). Additionally, this study extended the application of the sensor to detect pentoxifylline, an active pharmaceutical ingredient in pediatric medicines. These results underscore the taste sensor's value as an additional tool for early-stage assessment and prediction of bitterness in non-charged pharmaceuticals.
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Affiliation(s)
- Zeyu Zhao
- Graduate School of Information Science and Electrical Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan (T.O.)
| | - Fang Song
- Graduate School of Information Science and Electrical Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan (T.O.)
| | - Shunsuke Kimura
- Research and Development Center for Five-Sense Devices, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan
- Faculty of Nutritional Sciences, Nakamura Gakuen University, 5-7-1 Befu, Jonan-ku, Fukuoka 814-0198, Japan
- Food and Health Innovation Center, Nakamura Gakuen University, 5-7-1 Befu, Jonan-ku, Fukuoka 814-0198, Japan
| | - Takeshi Onodera
- Graduate School of Information Science and Electrical Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan (T.O.)
| | - Takahiro Uchida
- Food and Health Innovation Center, Nakamura Gakuen University, 5-7-1 Befu, Jonan-ku, Fukuoka 814-0198, Japan
- Faculty of Pharmaceutical Science, Mukogawa Women’s University, 11-68 Koshien 9-Bancho, Nishimiya 663-8179, Japan
| | - Kiyoshi Toko
- Research and Development Center for Five-Sense Devices, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan
- Food and Health Innovation Center, Nakamura Gakuen University, 5-7-1 Befu, Jonan-ku, Fukuoka 814-0198, Japan
- Institute for Advanced Study, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan
- Graduate School of Nutritional Sciences, Nakamura Gakuen University, 5-7-1 Befu, Jonan-ku, Fukuoka 814-0198, Japan
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Cao F, Zhang HL, Guo C, Xu XL, Yuan Q. Targeting oxidative stress with natural products: A novel strategy for esophageal cancer therapy. World J Gastrointest Oncol 2024; 16:287-299. [PMID: 38425393 PMCID: PMC10900143 DOI: 10.4251/wjgo.v16.i2.287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 12/12/2023] [Accepted: 01/12/2024] [Indexed: 02/02/2024] Open
Abstract
Esophageal cancer (ESC) is a malignant tumor that originates from the mucosal epithelium of the esophagus and is part of the digestive tract. Although the exact pathogenesis of ESC has not been fully elucidated, excessive oxidative stress is an important characteristic that leads to the development of many cancers. Abnormal expression of several proteins and transcription factors contributes to oxidative stress in ESCs, which alters the growth and proliferation of ESCs and promotes their metastasis. Natural compounds, including alkaloids, terpenes, polyphenols, and xanthine compounds, can inhibit reactive oxygen species production in ESCs. These compounds reduce oxidative stress levels and subsequently inhibit the occurrence and progression of ESC through the regulation of targets and pathways such as the cytokine interleukins 6 and 10, superoxide dismutase, the NF-+ACY-kappa+ADs-B/MAPK pathway, and the mammalian Nrf2/ARE target pathway. Thus, targeting tumor oxidative stress has become a key focus in anti-ESC therapy. This review discusses the potential of Natural products (NPs) for treating ESCs and summarizes the application prospects of oxidative stress as a new target for ESC treatment. The findings of this review provide a reference for drug development targeting ESCs. Nonetheless, further high-quality studies will be necessary to determine the clinical efficacy of these various NPs.
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Affiliation(s)
- Fang Cao
- Department of Rehabilitation III, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, Sichuan Province, China
| | - Han-Ling Zhang
- Department of Rehabilitation, Chongqing Fuling District Maternal and Child Health Hospital, Chongqing 408000, China
| | - Cui Guo
- Department of Rehabilitation, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, Sichuan Province, China
| | - Xue-Liang Xu
- Department of Rehabilitation III, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, Sichuan Province, China
| | - Qiang Yuan
- Department of Rehabilitation III, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, Sichuan Province, China
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7
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Stolfa I, Page C. Phosphodiesterase inhibitors and lung diseases. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2023; 98:55-81. [PMID: 37524492 DOI: 10.1016/bs.apha.2023.05.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/02/2023]
Abstract
Phosphodiesterase enzymes (PDE) have long been known as regulators of cAMP and cGMP, second messengers involved in various signaling pathways and expressed in a variety of cell types implicated in respiratory diseases such as airway smooth muscle and inflammatory cells making them a key target for the treatment of lung diseases as chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, and pulmonary hypertension (PH). The first reported PDE inhibitor was the xanthine, theophylline, described as a non-specific PDE inhibitor and whilst this drug is effective, it also has a range of unwanted side effects. In an attempt to improve the therapeutic window of xanthines, a number of selective PDE inhibitors have been developed for the treatment of respiratory diseases with only the selective PDE 4 inhibitor, roflumilast, being approved for the treatment of severe COPD. However, roflumilast also has a very narrow therapeutic window due to a number of important doses limiting side effects, particularly in the gastrointestinal tract. However, there continues to be research carried out in this field to identify improved selective PDE inhibitors, both by targeting other PDE subtypes (e.g., PDE 7 found in a number of inflammatory and immune cells) and through development of selective PDE inhibitors for pulmonary administration to reduce systemic exposure and improve the side effect profile. This approach has been exemplified by the development of ensifentrine, a dual PDE 3-PDE 4 inhibitor, an inhaled drug that has recently completed two successful Phase III clinical trials in patients with COPD.
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Affiliation(s)
- Ivana Stolfa
- Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College, London, United Kingdom
| | - Clive Page
- Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College, London, United Kingdom.
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8
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Alomar SY. Studying the Mechanism of Interaction of Doxofylline with Human Lysozyme: A Biophysical and In Silico Approach. Molecules 2023; 28:molecules28083462. [PMID: 37110695 PMCID: PMC10146846 DOI: 10.3390/molecules28083462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 03/29/2023] [Accepted: 04/01/2023] [Indexed: 04/29/2023] Open
Abstract
In this study, multiple spectroscopic and computational methods were utilized to investigate the binding mechanism of doxofylline with lysozyme. The in vitro methods were used to obtain the binding kinetics and thermodynamics. UV-vis spectroscopy indicated the formation of complex between doxofylline and lysozyme. The Gibb's free energy and binding constant from UV-vis data was obtained as -7.20 kcal M-1 and 1.929 × 105 M-1, respectively. Doxofylline successfully quenched the fluorescence of lysozyme, confirming the formation of complex. The kq and Ksv values for the quenching of lysozyme's fluorescence by doxofylline were 5.74 × 1011 M-1 s-1 and 3.32 × 103 M-1, respectively. These values signified a moderate binding affinity between doxofylline and lysozyme. In synchronous spectroscopy, red shifts were observed for indicating the changes in microenvironment of lysozyme following the binding of doxofylline. The secondary structural analysis was determined using circular dichroism (CD) which revealed an increase in % α-helical as a result of doxofylline interaction. The binding affinity and flexibility of lysozyme upon complexation have been revealed via molecular docking and molecular dynamic (MD) simulations, respectively. According to the many parameters of the MD simulation, the lysozyme-doxofylline complex was stable under physiological conditions. All during the simulation time, hydrogen bonds were continuously present. The MM-PBSA binding energy for lysozyme and doxofylline binding was found to be -30.55 kcal mol-1.
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Affiliation(s)
- Suliman Yousef Alomar
- Zoology Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
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Xu L, Zhang M, Pan J, Xu X, Zhang Y, Han X, Yin L, Chen L, Ren J, Yu J, Zhang Y, Liang G, Zhang Y. Doxofylline ameliorates liver fibrosis by regulating the ferroptosis signaling pathway. Front Pharmacol 2023; 14:1135366. [PMID: 37007035 PMCID: PMC10063813 DOI: 10.3389/fphar.2023.1135366] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Accepted: 03/08/2023] [Indexed: 03/19/2023] Open
Abstract
Liver fibrosis, a compensatory repair response to chronic liver injury, is caused by various pathogenic factors, and hepatic stellate cell (HSC) activation and phenotypic transformation are regarded as key events in its progression. Ferroptosis, a novel form of programmed cell death, is also closely related to different pathological processes, including those associated with liver diseases. Here, we investigated the effect of doxofylline (DOX), a xanthine derivative with potent anti-inflammatory activity, on liver fibrosis as well as the associated mechanism. Our results indicated that in mice with CCl4-induced liver fibrosis, DOX attenuated hepatocellular injury and the levels of liver fibrosis indicators, inhibited the TGF-β/Smad signaling pathway, and significantly downregulated the expression of HSC activation markers, both in vitro and in vivo. Furthermore, inducing ferroptosis in activated HSCs was found to be critical for its anti-liver fibrosis effect. More importantly, ferroptosis inhibition using the specific inhibitor, deferoxamine (DFO) not only abolished DOX-induced ferroptosis, but also led to resistance to the anti-liver fibrosis effect of DOX in HSCs. In summary, our results showed an association between the protective effect of DOX against liver fibrosis and HSC ferroptosis. Thus, DOX may be a promising anti-hepatic fibrosis agent.
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Affiliation(s)
- Lenan Xu
- Affiliated Yongkang First People’s Hospital, School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, China
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Meiling Zhang
- Affiliated Yongkang First People’s Hospital, School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, China
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Junzhi Pan
- Affiliated Yongkang First People’s Hospital, School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Xiangwei Xu
- Affiliated Yongkang First People’s Hospital, School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Yawen Zhang
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Xue Han
- Zhejiang Provincial Key Laboratory of Laboratory Animals and Safety Research, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Lina Yin
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Lingfeng Chen
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Juan Ren
- School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Jie Yu
- School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Yanmei Zhang
- School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Guang Liang
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
- *Correspondence: Guang Liang, ; Yi Zhang,
| | - Yi Zhang
- Affiliated Yongkang First People’s Hospital, School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, China
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China
- *Correspondence: Guang Liang, ; Yi Zhang,
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Aprile S, Colombo G, Serafini M, Di Paola R, Pisati F, Bhela IP, Cuzzocrea S, Grosa G, Pirali T. An Unexpected Deuterium-Induced Metabolic Switch in Doxophylline. ACS Med Chem Lett 2022; 13:1278-1285. [PMID: 35978700 PMCID: PMC9377007 DOI: 10.1021/acsmedchemlett.2c00166] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 07/11/2022] [Indexed: 01/03/2023] Open
Abstract
Precision deuteration has become part of the medicinal chemist's toolbox, but its usefulness can be undermined by unpredictable metabolic switch effects. Herein we report the deuteration of doxophylline, a drug used in the treatment of asthma and COPD that undergoes extensive oxidative metabolism. Labeling of the main metabolic soft spots triggered an unexpected multidirectional metabolic switch that, while not improving the pharmacokinetic parameters, changed the metabolic scenario and, in turn, the pharmacodynamic features in two murine models of lung injury.
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Affiliation(s)
- Silvio Aprile
- Department
of Pharmaceutical Sciences, Università
del Piemonte Orientale, 28100 Novara, Italy
| | - Giorgia Colombo
- Department
of Pharmaceutical Sciences, Università
del Piemonte Orientale, 28100 Novara, Italy
| | - Marta Serafini
- Department
of Pharmaceutical Sciences, Università
del Piemonte Orientale, 28100 Novara, Italy
| | - Rosanna Di Paola
- Department
of Chemical, Biological, Pharmaceutical and Environmental Sciences, Università di Messina, 98166 Messina, Italy
| | - Federica Pisati
- Histopathology
Unit, Cogentech S.C.a.R.L., 20139 Milan, Italy
| | - Irene Preet Bhela
- Department
of Pharmaceutical Sciences, Università
del Piemonte Orientale, 28100 Novara, Italy
| | - Salvatore Cuzzocrea
- Department
of Chemical, Biological, Pharmaceutical and Environmental Sciences, Università di Messina, 98166 Messina, Italy
| | - Giorgio Grosa
- Department
of Pharmaceutical Sciences, Università
del Piemonte Orientale, 28100 Novara, Italy
| | - Tracey Pirali
- Department
of Pharmaceutical Sciences, Università
del Piemonte Orientale, 28100 Novara, Italy
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11
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Styrvold M, Heggset Sterten AJ, Shrestha S, Dhakal S, Harstad I. An audit of patients admitted to hospital in Nepal for COPD exacerbation. SAGE Open Med 2022; 10:20503121221085087. [PMID: 35321460 PMCID: PMC8935543 DOI: 10.1177/20503121221085087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 02/14/2022] [Indexed: 11/17/2022] Open
Abstract
Objectives: Chronic obstructive pulmonary disease is a large and increasing problem in low- and middle-income countries; Nepal is no exception. We aimed to obtain information on patient characteristics and the level of care provided to patients admitted for acute exacerbation of chronic obstructive pulmonary disease in two Nepalese hospitals and to compare the given care with the Global Initiative for Chronic Obstructive Lung Disease guidelines. Methods: This was a cross-sectional, observational, descriptive study. All patients admitted to two Nepalese hospitals due to acute exacerbation of chronic obstructive pulmonary disease between 18 February and 5 April 2019 were asked to participate. Results: In total, 108 patients with a median age of 70 years participated. Fifty-three (42.7%) were male, 80 (74.8%) were former smokers, and 46 (45.1%) were farmers. Using the Global Initiative for Chronic Obstructive Lung Disease A-D classification, 97 (90.6%) of the patients were classified in group D. All the patients received supplementary oxygen treatment and 103 (95.4%) were treated with short-acting beta2 agonists. A total of 105 (97.2%) patients received antibiotics, and 80 (74.5%) received systemic corticosteroids. The majority was discharged with triple therapy including long-acting muscarinic antagonist, long-acting beta2 agonist, and inhaled corticosteroids, and 72 (75.8%) were discharged with long-term oxygen treatment. Conclusion: All elements of the Global Initiative for Chronic Obstructive Lung Disease guidelines were applied. However, due to a lack of information, it cannot be concluded whether the treatment was provided on the correct indications. The average patient received almost all the treatment alternatives available. This might indicate a very sick population or over-treatment.
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Affiliation(s)
- Marte Styrvold
- Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
| | - Ane Jonette Heggset Sterten
- Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
| | - Sudeep Shrestha
- Department of Internal Medicine, Dhulikhel Hospital, Dhulikhel, Nepal
| | - Subodh Dhakal
- Department of Internal Medicine, Kathmandu Medical College, Kathmandu, Nepal
| | - Ingunn Harstad
- Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Pulmonary Medicine, St. Olav’s University Hospital, Trondheim, Norway
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12
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Zhan Z, Ma Y, Huang K, Liang C, Mao X, Zhang Y, Ren X, Lei J, Chen Y, Yang T, Wang C. Methylxanthine Treatment in Patients Hospitalized for Acute Exacerbation of Chronic Obstructive Pulmonary Disease in China: A Real-World Study Using Propensity Score Matching Analysis. Front Pharmacol 2022; 13:802123. [PMID: 35145412 PMCID: PMC8821534 DOI: 10.3389/fphar.2022.802123] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 01/06/2022] [Indexed: 12/25/2022] Open
Abstract
Background: Although medical guidelines discourage the use of methylxanthines in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD), they are still widely used in clinical practice. This study investigated the real-world use of methylxanthines in the management of AECOPD.Methods: Patient data from the Acute exacerbation of Chronic obstructive pulmonary disease Using REgistry data (ACURE, NCT02657525) study database were screened. Enrolled patients were divided into treatment and control groups. Propensity score (PS) matching and Cox regression analyses were used to minimize confounding factors and determine the association between methylxanthine treatment and the length of stay (LOS).Results: Among the 2088 eligible patients, 1,563 (74.9%) were in the methylxanthine treatment group. Patients treated with methylxanthines had more severe respiratory symptoms and worse lung function than those in the control group. Doxophylline was the most commonly used methylxanthine in both secondary and tertiary hospitals. After PS matching, 966 patients were equally divided into two groups. The LOS of patients in the two groups was similar [median: 8 days, interquartile range (IQR): 7–11 days, p = 0.730]. Patients in the treatment group (median: 8, IQR: 4–12) had a more significant decrease in the COPD Assessment Test score from admission to discharge than those in the control group (median: 6, IQR: 2–10, p < 0.001). Among all matched patients, the LOS was not significantly associated with methylxanthine treatment [adjusted hazard ratio (HR): 1.02, 95% confidence intervals (CIs): 0.89–1.16]. However, in the subgroup analysis, methylxanthines were significantly associated with a short LOS in patients with blood eosinophil count >4% (adjusted HR: 1.56, 95% CIs: 1.12–2.17).Conclusion: This study revealed that methylxanthines, especially doxophylline, are widely used in China. Methylxanthines were effective in improving symptoms in AECOPD patients. Higher blood eosinophil count may be associated with a better efficacy of methylxanthine treatment.
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Affiliation(s)
- Zijie Zhan
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yiming Ma
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ke Huang
- Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, China
- National Clinical Research Center for Respiratory Disease, Beijing, China
- Institute of Respiratory Medicine, Chinese Academy of Medical Science, Beijing, China
| | - Chen Liang
- Chinese Alliance for Respiratory Diseases in Primary Care, Beijing, China
| | - Xihua Mao
- Chinese Alliance for Respiratory Diseases in Primary Care, Beijing, China
| | - Yaowen Zhang
- Chinese Alliance for Respiratory Diseases in Primary Care, Beijing, China
| | - Xiaoxia Ren
- Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, China
- National Clinical Research Center for Respiratory Disease, Beijing, China
- Institute of Respiratory Medicine, Chinese Academy of Medical Science, Beijing, China
| | - Jieping Lei
- Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, China
- National Clinical Research Center for Respiratory Disease, Beijing, China
- Institute of Respiratory Medicine, Chinese Academy of Medical Science, Beijing, China
| | - Yan Chen
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Yan Chen, ; Ting Yang,
| | - Ting Yang
- Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, China
- National Clinical Research Center for Respiratory Disease, Beijing, China
- Institute of Respiratory Medicine, Chinese Academy of Medical Science, Beijing, China
- *Correspondence: Yan Chen, ; Ting Yang,
| | - Chen Wang
- Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, China
- National Clinical Research Center for Respiratory Disease, Beijing, China
- Institute of Respiratory Medicine, Chinese Academy of Medical Science, Beijing, China
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Fierro V, Piscitelli AL, Battaglia E, Fiocchi A. Doxofylline for Pediatric Asthma Steps 1-4. Pediatric Asthma: New Role for an Old Drug. Front Pediatr 2022; 10:772704. [PMID: 35813377 PMCID: PMC9256910 DOI: 10.3389/fped.2022.772704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 03/08/2022] [Indexed: 11/13/2022] Open
Abstract
The panoply of anti-asthma drugs for children between 6 and 18 years is not limited to those reported in the guidelines. In this review, we will re-assess the role of doxofylline, a xanthine characterized by a much higher handling than that of theophylline, as add-on treatment in pediatric asthma grade 1-4. Ten studies evaluated doxofylline in the treatment of asthma of patients non-responsive to the first-line inhaled corticosteroids. Of these, two included children and one was exclusively pediatric. According to their results, doxofylline exerts a powerful bronchodilator and anti-inflammatory activity, which can be exploited when the inhaled oral corticosteroids are not sufficient to get the desired effect of reducing symptoms. Unlike theophylline, doxofylline does not require blood testing. It can be administered together with or as an alternative to a series of other drugs considered in additional therapy.
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Affiliation(s)
- Vincenzo Fierro
- Predictive and Preventive Medicine Research Unit, Multifactorial and Systemic Diseases Research Area, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Anna Lucia Piscitelli
- Predictive and Preventive Medicine Research Unit, Multifactorial and Systemic Diseases Research Area, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | | | - Alessandro Fiocchi
- Predictive and Preventive Medicine Research Unit, Multifactorial and Systemic Diseases Research Area, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
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14
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Chen H, Yang N, Yang Y, Zheng Y, Xu M, Zhang H, Liu Y, Shen W, Li J. Doxofylline Protects Gram-Negative Pathogens against Antibiotic-Mediated Killing. ACS Infect Dis 2021; 7:3241-3253. [PMID: 34851627 DOI: 10.1021/acsinfecdis.1c00417] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Given the growing rate of Gram-negative bacterial infections, antibiotics are now frequently prescribed for various respiratory diseases. Doxofylline is a newer generation xanthine with both bronchodilating and anti-inflammatory activities, but its influence on antibiotics remains poorly understood. Here, we first report the discovery of doxofylline-induced high minimum inhibitory concentrations of antibiotics. We also showed that doxofylline blocked antimicrobial-mediated killing for Gram-negative pathogens in vitro and in murine lung infection models in vivo. By combining efflux pump inhibition tests, gene expression analyses, and using the gene tolC knockout strain, we found that doxofylline positively regulated gene expression of the AcrAB-TolC efflux pump and attenuated the effect of doxofylline on antibacterial activities in ΔtolC mutants. Notably, doxofylline-mediated protection correlated with decreased reactive oxygen species (ROS) production. Collectively, our study indicates that doxofylline protects Gram-negative bacteria from antimicrobial lethality by regulating the AcrAB-TolC efflux pump in a TolC-dependent manner and suppressing antibiotic-induced ROS accumulation. These results suggest caution when using antibiotics alongside doxofylline in clinical treatment.
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Affiliation(s)
- Haoran Chen
- Department of Infectious Disease, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Ning Yang
- Department of Infectious Disease, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Yi Yang
- Department of Infectious Disease, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Yahong Zheng
- Department of Infectious Disease, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Mengran Xu
- Department of Infectious Disease, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Hui Zhang
- Department of Infectious Disease, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Yanyan Liu
- Department of Infectious Disease, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
- Anhui Center for Surveillance of Bacterial Resistance, Hefei, Anhui 230022, China
- Institute of Bacterial Resistance, Anhui Medical University, Hefei, Anhui 230022, China
| | - Weihua Shen
- Department of Special Clinic, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Jiabin Li
- Department of Infectious Disease, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
- Department of Molecular Biology, Anhui Center for Surveillance of Bacterial Resistance, Hefei, Anhui 230022, China
- Anhui Center for Surveillance of Bacterial Resistance, Hefei, Anhui 230022, China
- Institute of Bacterial Resistance, Anhui Medical University, Hefei, Anhui 230022, China
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15
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Towards Splicing Therapy for Lysosomal Storage Disorders: Methylxanthines and Luteolin Ameliorate Splicing Defects in Aspartylglucosaminuria and Classic Late Infantile Neuronal Ceroid Lipofuscinosis. Cells 2021; 10:cells10112813. [PMID: 34831035 PMCID: PMC8616534 DOI: 10.3390/cells10112813] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 10/01/2021] [Accepted: 10/15/2021] [Indexed: 12/22/2022] Open
Abstract
Splicing defects caused by mutations in the consensus sequences at the borders of introns and exons are common in human diseases. Such defects frequently result in a complete loss of function of the protein in question. Therapy approaches based on antisense oligonucleotides for specific gene mutations have been developed in the past, but they are very expensive and require invasive, life-long administration. Thus, modulation of splicing by means of small molecules is of great interest for the therapy of genetic diseases resulting from splice-site mutations. Using minigene approaches and patient cells, we here show that methylxanthine derivatives and the food-derived flavonoid luteolin are able to enhance the correct splicing of the AGA mRNA with a splice-site mutation c.128-2A>G in aspartylglucosaminuria, and result in increased AGA enzyme activity in patient cells. Furthermore, we also show that one of the most common disease causing TPP1 gene variants in classic late infantile neuronal ceroid lipofuscinosis may also be amenable to splicing modulation using similar substances. Therefore, our data suggest that splice-modulation with small molecules may be a valid therapy option for lysosomal storage disorders.
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16
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Kricker JA, Page CP, Gardarsson FR, Baldursson O, Gudjonsson T, Parnham MJ. Nonantimicrobial Actions of Macrolides: Overview and Perspectives for Future Development. Pharmacol Rev 2021; 73:233-262. [PMID: 34716226 DOI: 10.1124/pharmrev.121.000300] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Macrolides are among the most widely prescribed broad spectrum antibacterials, particularly for respiratory infections. It is now recognized that these drugs, in particular azithromycin, also exert time-dependent immunomodulatory actions that contribute to their therapeutic benefit in both infectious and other chronic inflammatory diseases. Their increased chronic use in airway inflammation and, more recently, of azithromycin in COVID-19, however, has led to a rise in bacterial resistance. An additional crucial aspect of chronic airway inflammation, such as chronic obstructive pulmonary disease, as well as other inflammatory disorders, is the loss of epithelial barrier protection against pathogens and pollutants. In recent years, azithromycin has been shown with time to enhance the barrier properties of airway epithelial cells, an action that makes an important contribution to its therapeutic efficacy. In this article, we review the background and evidence for various immunomodulatory and time-dependent actions of macrolides on inflammatory processes and on the epithelium and highlight novel nonantibacterial macrolides that are being studied for immunomodulatory and barrier-strengthening properties to circumvent the risk of bacterial resistance that occurs with macrolide antibacterials. We also briefly review the clinical effects of macrolides in respiratory and other inflammatory diseases associated with epithelial injury and propose that the beneficial epithelial effects of nonantibacterial azithromycin derivatives in chronic inflammation, even given prophylactically, are likely to gain increasing attention in the future. SIGNIFICANCE STATEMENT: Based on its immunomodulatory properties and ability to enhance the protective role of the lung epithelium against pathogens, azithromycin has proven superior to other macrolides in treating chronic respiratory inflammation. A nonantibiotic azithromycin derivative is likely to offer prophylactic benefits against inflammation and epithelial damage of differing causes while preserving the use of macrolides as antibiotics.
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Affiliation(s)
- Jennifer A Kricker
- EpiEndo Pharmaceuticals, Reykjavik, Iceland (J.A.K., C.P.P., F.R.G., O.B., T.G., M.J.P.); Stem Cell Research Unit, Biomedical Center, University of Iceland, Reykjavik, Iceland (J.A.K., T.G.); Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, United Kingdom (C.P.P.); Department of Respiratory Medicine (O.B.), Department of Laboratory Hematology (T.G.), Landspitali-University Hospital, Reykjavik, Iceland; Faculty of Biochemistry, Chemistry and Pharmacy, JW Goethe University Frankfurt am Main, Germany (M.J.P.)
| | - Clive P Page
- EpiEndo Pharmaceuticals, Reykjavik, Iceland (J.A.K., C.P.P., F.R.G., O.B., T.G., M.J.P.); Stem Cell Research Unit, Biomedical Center, University of Iceland, Reykjavik, Iceland (J.A.K., T.G.); Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, United Kingdom (C.P.P.); Department of Respiratory Medicine (O.B.), Department of Laboratory Hematology (T.G.), Landspitali-University Hospital, Reykjavik, Iceland; Faculty of Biochemistry, Chemistry and Pharmacy, JW Goethe University Frankfurt am Main, Germany (M.J.P.)
| | - Fridrik Runar Gardarsson
- EpiEndo Pharmaceuticals, Reykjavik, Iceland (J.A.K., C.P.P., F.R.G., O.B., T.G., M.J.P.); Stem Cell Research Unit, Biomedical Center, University of Iceland, Reykjavik, Iceland (J.A.K., T.G.); Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, United Kingdom (C.P.P.); Department of Respiratory Medicine (O.B.), Department of Laboratory Hematology (T.G.), Landspitali-University Hospital, Reykjavik, Iceland; Faculty of Biochemistry, Chemistry and Pharmacy, JW Goethe University Frankfurt am Main, Germany (M.J.P.)
| | - Olafur Baldursson
- EpiEndo Pharmaceuticals, Reykjavik, Iceland (J.A.K., C.P.P., F.R.G., O.B., T.G., M.J.P.); Stem Cell Research Unit, Biomedical Center, University of Iceland, Reykjavik, Iceland (J.A.K., T.G.); Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, United Kingdom (C.P.P.); Department of Respiratory Medicine (O.B.), Department of Laboratory Hematology (T.G.), Landspitali-University Hospital, Reykjavik, Iceland; Faculty of Biochemistry, Chemistry and Pharmacy, JW Goethe University Frankfurt am Main, Germany (M.J.P.)
| | - Thorarinn Gudjonsson
- EpiEndo Pharmaceuticals, Reykjavik, Iceland (J.A.K., C.P.P., F.R.G., O.B., T.G., M.J.P.); Stem Cell Research Unit, Biomedical Center, University of Iceland, Reykjavik, Iceland (J.A.K., T.G.); Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, United Kingdom (C.P.P.); Department of Respiratory Medicine (O.B.), Department of Laboratory Hematology (T.G.), Landspitali-University Hospital, Reykjavik, Iceland; Faculty of Biochemistry, Chemistry and Pharmacy, JW Goethe University Frankfurt am Main, Germany (M.J.P.)
| | - Michael J Parnham
- EpiEndo Pharmaceuticals, Reykjavik, Iceland (J.A.K., C.P.P., F.R.G., O.B., T.G., M.J.P.); Stem Cell Research Unit, Biomedical Center, University of Iceland, Reykjavik, Iceland (J.A.K., T.G.); Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, United Kingdom (C.P.P.); Department of Respiratory Medicine (O.B.), Department of Laboratory Hematology (T.G.), Landspitali-University Hospital, Reykjavik, Iceland; Faculty of Biochemistry, Chemistry and Pharmacy, JW Goethe University Frankfurt am Main, Germany (M.J.P.)
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17
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Liu CY, Wu JH, Chen ZY, Zhang Y, Huang CL, Lin AM, Xu XT, Gao XH. Effect of Doxofylline on Reducing the Inflammatory Response in Mechanically Ventilated Rats with Chronic Obstructive Pulmonary Disease. Int J Chron Obstruct Pulmon Dis 2021; 16:2375-2383. [PMID: 34429595 PMCID: PMC8378927 DOI: 10.2147/copd.s315639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 08/02/2021] [Indexed: 12/03/2022] Open
Abstract
Objective To evaluate the effect of doxofylline on reducing the inflammatory response in mechanically ventilated rats with chronic obstructive pulmonary disease (COPD). Methods A total of 40 eight-week-old male Sprague Dawley rats were randomly divided into four groups of 10 rats each: a control group (group C), a model group (group M), a model + natural saline group (group N), and a doxofylline group (group D). Then mechanical ventilation, drug intervention, and the extraction of the experimental material were performed in each group. Pulmonary tissue samples were taken after 120 minutes of mechanical ventilation and the pulmonary histopathological changes and the wet/dry (W/D) weight ratio of the pulmonary tissue were identified. The levels of tumor necrosis factor α (TNF-α) and interleukin 10 (IL-10) were detected using an enzyme-linked immunosorbent assay, and the expression levels of c-Jun-N-terminal kinase (JNK) and phosphorylated c-Jun N-terminal kinase (p-JNK) were detected using immunohistochemistry. Results Compared with group C, the pulmonary histopathology in groups M, N, and D showed typical changes associated with COPD. Furthermore, the W/D weight ratio and levels of TNF-α, JNK, and p-JNK in the pulmonary tissue increased in groups M, N, and D (P < 0.05), while the levels of IL-10 decreased (P < 0.05). Compared with group M, no statistically significant changes in the above indicators were detected in the pulmonary tissue of group N (P > 0.05). Compared with group N, the W/D weight ratio and levels of TNF-α, JNK, and p-JNK in the pulmonary tissue decreased in group D (P < 0.05), while the levels of IL-10 increased (P < 0.05). Conclusion Doxofylline might attenuate pulmonary inflammatory responses in mechanically ventilated rats with COPD, and the JNK/stress-activated protein kinase signaling pathway is involved in doxofylline’s inhibition of inflammatory responses in the pulmonary tissue of rats with COPD.
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Affiliation(s)
- Chu-Yun Liu
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, People's Republic of China
| | - Jian-Hua Wu
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, People's Republic of China
| | - Zhi-Yuan Chen
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, People's Republic of China
| | - Yi Zhang
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, People's Republic of China
| | - Chun-Ling Huang
- Department of Laboratory, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, People's Republic of China
| | - Ai-Mei Lin
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, People's Republic of China
| | - Xiao-Ting Xu
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, People's Republic of China
| | - Xiao-Hua Gao
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, People's Republic of China
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18
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Wu YJ, Meanwell NA. Geminal Diheteroatomic Motifs: Some Applications of Acetals, Ketals, and Their Sulfur and Nitrogen Homologues in Medicinal Chemistry and Drug Design. J Med Chem 2021; 64:9786-9874. [PMID: 34213340 DOI: 10.1021/acs.jmedchem.1c00790] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Acetals and ketals and their nitrogen and sulfur homologues are often considered to be unconventional and potentially problematic scaffolding elements or pharmacophores for the design of orally bioavailable drugs. This opinion is largely a function of the perception that such motifs might be chemically unstable under the acidic conditions of the stomach and upper gastrointestinal tract. However, even simple acetals and ketals, including acyclic molecules, can be sufficiently robust under acidic conditions to be fashioned into orally bioavailable drugs, and these structural elements are embedded in many effective therapeutic agents. The chemical stability of molecules incorporating geminal diheteroatomic motifs can be modulated by physicochemical design principles that include the judicious deployment of proximal electron-withdrawing substituents and conformational restriction. In this Perspective, we exemplify geminal diheteroatomic motifs that have been utilized in the discovery of orally bioavailable drugs or drug candidates against the backdrop of understanding their potential for chemical lability.
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Affiliation(s)
- Yong-Jin Wu
- Small Molecule Drug Discovery, Bristol Myers Squibb Research and Early Development, 100 Binney Street, Cambridge, Massachusetts 02142, United States
| | - Nicholas A Meanwell
- Department of Discovery and Chemistry and Molecular Technologies, Bristol-Myers Squibb PRI, PO Box 4000, Princeton, New Jersey 08543-4000, United States
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19
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Matera MG, Ora J, Cavalli F, Rogliani P, Cazzola M. New Avenues for Phosphodiesterase Inhibitors in Asthma. J Exp Pharmacol 2021; 13:291-302. [PMID: 33758554 PMCID: PMC7979323 DOI: 10.2147/jep.s242961] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Accepted: 02/10/2021] [Indexed: 12/16/2022] Open
Abstract
Introduction Phosphodiesterases (PDEs) are isoenzymes ubiquitously expressed in the lungs where they catalyse cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (GMP), which are fundamental second messengers in asthma, thereby regulating the intracellular concentrations of these cyclic nucleotides, their signaling pathways and, consequently, myriad biological responses. The superfamily of PDEs is composed of 11 families with a distinct substrate specificity, molecular structure and subcellular localization. Experimental studies indicate a possible role in asthma mainly for PDE3, PDE4, PDE5 and PDE7. Consequently, drugs that inhibit PDEs may offer novel therapeutic options for the treatment of this disease. Areas Covered In this article, we describe the progress made in recent years regarding the possibility of using PDE inhibitors in the treatment of asthma. Expert Opinion Many data indicate the potential benefits of PDE inhibitors as an add-on treatment especially in severe asthma due to their bronchodilator and/or anti-inflammatory activity, but no compound has yet reached the market as asthma treatment mainly because of their limited tolerability. Therefore, there is a growing interest in developing new PDE inhibitors with an improved safety profile. In particular, the research is focused on the development of drugs capable of interacting simultaneously with different PDEs, or to be administered by inhalation. CHF 6001 and RPL554 are the only molecules that currently are under clinical development but there are several new agents with interesting pharmacological profiles. It will be stimulating to assess the impact of such agents on individual treatable traits in specially designed studies.
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Affiliation(s)
- Maria Gabriella Matera
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Josuel Ora
- Respiratory Diseases Unit, "Tor Vergata" University Hospital, Rome, Italy
| | - Francesco Cavalli
- Respiratory Diseases Unit, "Tor Vergata" University Hospital, Rome, Italy
| | - Paola Rogliani
- Respiratory Diseases Unit, "Tor Vergata" University Hospital, Rome, Italy.,Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Mario Cazzola
- Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy
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Siddiqui S, Ameen F, Kausar T, Nayeem SM, Ur Rehman S, Tabish M. Biophysical insight into the binding mechanism of doxofylline to bovine serum albumin: An in vitro and in silico approach. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2021; 249:119296. [PMID: 33338935 DOI: 10.1016/j.saa.2020.119296] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 11/03/2020] [Accepted: 11/29/2020] [Indexed: 05/16/2023]
Abstract
Insight into the mechanistic binding of bovine serum albumin (BSA) with doxofylline can layout pivotal enlightenment with relevance to pharmacokinetics and pharmacodynamics properties. Herein, many spectroscopic techniques and computational methods had been employed to interpret the structural and binding dynamics of BSA-doxofylline interaction. Doxofylline quenched the intrinsic fluorescence of BSA by static quenching. The stoichiometry and the binding constant of the BSA-doxofylline complex were 1:1 and in the order of 103 M-1. It was also concluded that the binding process was spontaneous and exothermic, primarily based on the thermodynamic study. Circular dichroism and three-dimensional excitation-emission matrix fluorescence results concluded pronounced conformational and microenvironmental changes in BSA structure on binding with doxofylline. The influence of metal ions and vitamins on the binding affinity of the BSA-doxofylline system were also explored. The in vitro findings were further supported by in silico analysis. With a score value of -6.25 kcal/mol, molecular docking showed strong interactions. Molecular dynamics simulation interpretation also suggested the stable binding with lower deviation in the values of RMSD and RMSF obtained by uninterrupted long simulation run. These studies will propose the optimum potency of distribution of the doxofylline into the bloodstream for asthma treatment.
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Affiliation(s)
- Sharmin Siddiqui
- Department of Biochemistry, Faculty of Life Sciences, A.M. University, Aligarh, UP 202002, India
| | - Faisal Ameen
- Department of Biochemistry, Faculty of Life Sciences, A.M. University, Aligarh, UP 202002, India
| | - Tasneem Kausar
- Department of Chemistry, Faculty of Science, A.M. University, Aligarh, U.P. 202002, India
| | - Shahid M Nayeem
- Department of Chemistry, Faculty of Science, A.M. University, Aligarh, U.P. 202002, India
| | - Sayeed Ur Rehman
- Department of Biochemistry, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi 110062, India
| | - Mohammad Tabish
- Department of Biochemistry, Faculty of Life Sciences, A.M. University, Aligarh, UP 202002, India.
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21
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Jiao P, Li W, Shen L, Li Y, Yu L, Liu Z. The protective effect of doxofylline against lipopolysaccharides (LPS)-induced activation of NLRP3 inflammasome is mediated by SIRT1 in human pulmonary bronchial epithelial cells. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2021; 48:687-694. [PMID: 32098511 DOI: 10.1080/21691401.2020.1730391] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Lung diseases are common health problems in many countries. The dysfunction of bronchial epithelial cells is important for the development of lung diseases. Recent progress reveals that inflammasome is the fundamental mechanism of epithelial activation. Here, we report the protective effect of doxofylline, a theophylline derivative agent, on lipopolysaccharides (LPS)-induced inflammatory response in bronchial epithelial cells. The presence of doxofylline reduces LPS-induced production of NO and PGE2. Doxofylline also inhibits LPS-induced production of mitochondrial ROS. Mechanistically, we show that doxofylline suppresses the expression of NOX4 induced by LPS. Doxofylline inhibits LPS-induced NLRP3-TXNIP inflammasome activation as revealed by its inhibitive effect on NLRP3, caspase 1 (P10 unit), and TXNIP induction as well as weakened induction of IL-1β and IL-18. Furthermore, we show that doxofylline ameliorates LPS-induced Sirtuin 1 (SIRT1) reduction. The silencing of SIRT1 abolishes the inhibitory effect of doxofylline on NLRP3 inflammasome activation. Collectively, our study demonstrates that doxofylline mitigates epithelial inflammation via amelioration of multiple cellular pathways, including NLRP3-TXNIP inflammasome activation.
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Affiliation(s)
- Peng Jiao
- Department of Emergency, Shangqiu First people's Hospital, Shangqiu, Henan, China
| | - Weiming Li
- The Third Affiliated Hospital, Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China
| | - Lin Shen
- Department of Emergency, Shangqiu First people's Hospital, Shangqiu, Henan, China
| | - Yan Li
- Department of Anesthesiology, Cangzhou Central Hospital, Cangzhou, Hebei, China
| | - Lili Yu
- Department of Anesthesiology, Cangzhou Central Hospital, Cangzhou, Hebei, China
| | - Zhaohui Liu
- Department of Anesthesiology, Cangzhou Central Hospital, Cangzhou, Hebei, China
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Zhao X, Ma H, Pan Q, Wang H, Qian X, Song P, Zou L, Mao M, Xia S, Ge G, Yang L. Theophylline Acetaldehyde as the Initial Product in Doxophylline Metabolism in Human Liver. Drug Metab Dispos 2020; 48:345-352. [PMID: 32086296 DOI: 10.1124/dmd.119.089565] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 01/30/2020] [Indexed: 11/22/2022] Open
Abstract
Doxophylline (DOXO) and theophylline are widely used as bronchodilators for treating asthma and chronic obstructive pulmonary disease, and DOXO has a better safety profile than theophylline. How DOXO's metabolism and disposition affect its antiasthmatic efficacy and safety remains to be explored. In this study, the metabolites of DOXO were characterized. A total of nine metabolites of DOXO were identified in vitro using liver microsomes from human and four other animal species. Among them, six metabolites were reported for the first time. The top three metabolites were theophylline acetaldehyde (M1), theophylline-7-acetic acid (M2), and etophylline (M4). A comparative analysis of DOXO metabolism in human using liver microsomes, S9 fraction, and plasma samples demonstrated the following: 1) The metabolism of DOXO began with a cytochrome P450 (P450)-mediated, rate-limiting step at the C ring and produced M1, the most abundant metabolite in human liver microsomes. However, in human plasma, the M1 production was rather low. 2) M1 was further converted to M2 and M4, the end products of DOXO metabolism in vivo, by non-P450 dismutase in the cytosol. This dismutation process also relied on the ratio of NADP+/NADPH in the cell. These findings for the first time elucidated the metabolic sites and routes of DOXO metabolism in human. SIGNIFICANCE STATEMENT: We systematically characterized doxophylline metabolism using in vitro and in vivo assays. Our findings evolved the understandings of metabolic sites and pathways for methylxanthine derivatives with the aldehyde functional group.
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Affiliation(s)
- Xiaohua Zhao
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (X.Z., Q.P., H.W., X.Q., P.S., L.Z., G.G., L.Y.); Center for Systems Pharmacokinetics, Shanghai University of Traditional Chinese Medicine, Shanghai, China (X.Z., Q.P., H.W., X.Q., P.S., L.Z., G.G., L.Y.); College of Basic Medical Sciences, Dalian Medical University, Liaoning, China (H.M.); Shanghai Research Institute of Acupuncture and Meridian, Shanghai, China (H.M.); and Respiratory Medicine Department, Central Hospital Affiliated to Shenyang Medical College, Liaoning, China (M.M., S.X.)
| | - Hong Ma
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (X.Z., Q.P., H.W., X.Q., P.S., L.Z., G.G., L.Y.); Center for Systems Pharmacokinetics, Shanghai University of Traditional Chinese Medicine, Shanghai, China (X.Z., Q.P., H.W., X.Q., P.S., L.Z., G.G., L.Y.); College of Basic Medical Sciences, Dalian Medical University, Liaoning, China (H.M.); Shanghai Research Institute of Acupuncture and Meridian, Shanghai, China (H.M.); and Respiratory Medicine Department, Central Hospital Affiliated to Shenyang Medical College, Liaoning, China (M.M., S.X.)
| | - Qiusha Pan
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (X.Z., Q.P., H.W., X.Q., P.S., L.Z., G.G., L.Y.); Center for Systems Pharmacokinetics, Shanghai University of Traditional Chinese Medicine, Shanghai, China (X.Z., Q.P., H.W., X.Q., P.S., L.Z., G.G., L.Y.); College of Basic Medical Sciences, Dalian Medical University, Liaoning, China (H.M.); Shanghai Research Institute of Acupuncture and Meridian, Shanghai, China (H.M.); and Respiratory Medicine Department, Central Hospital Affiliated to Shenyang Medical College, Liaoning, China (M.M., S.X.)
| | - Haiyi Wang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (X.Z., Q.P., H.W., X.Q., P.S., L.Z., G.G., L.Y.); Center for Systems Pharmacokinetics, Shanghai University of Traditional Chinese Medicine, Shanghai, China (X.Z., Q.P., H.W., X.Q., P.S., L.Z., G.G., L.Y.); College of Basic Medical Sciences, Dalian Medical University, Liaoning, China (H.M.); Shanghai Research Institute of Acupuncture and Meridian, Shanghai, China (H.M.); and Respiratory Medicine Department, Central Hospital Affiliated to Shenyang Medical College, Liaoning, China (M.M., S.X.)
| | - Xingkai Qian
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (X.Z., Q.P., H.W., X.Q., P.S., L.Z., G.G., L.Y.); Center for Systems Pharmacokinetics, Shanghai University of Traditional Chinese Medicine, Shanghai, China (X.Z., Q.P., H.W., X.Q., P.S., L.Z., G.G., L.Y.); College of Basic Medical Sciences, Dalian Medical University, Liaoning, China (H.M.); Shanghai Research Institute of Acupuncture and Meridian, Shanghai, China (H.M.); and Respiratory Medicine Department, Central Hospital Affiliated to Shenyang Medical College, Liaoning, China (M.M., S.X.)
| | - Peifang Song
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (X.Z., Q.P., H.W., X.Q., P.S., L.Z., G.G., L.Y.); Center for Systems Pharmacokinetics, Shanghai University of Traditional Chinese Medicine, Shanghai, China (X.Z., Q.P., H.W., X.Q., P.S., L.Z., G.G., L.Y.); College of Basic Medical Sciences, Dalian Medical University, Liaoning, China (H.M.); Shanghai Research Institute of Acupuncture and Meridian, Shanghai, China (H.M.); and Respiratory Medicine Department, Central Hospital Affiliated to Shenyang Medical College, Liaoning, China (M.M., S.X.)
| | - Liwei Zou
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (X.Z., Q.P., H.W., X.Q., P.S., L.Z., G.G., L.Y.); Center for Systems Pharmacokinetics, Shanghai University of Traditional Chinese Medicine, Shanghai, China (X.Z., Q.P., H.W., X.Q., P.S., L.Z., G.G., L.Y.); College of Basic Medical Sciences, Dalian Medical University, Liaoning, China (H.M.); Shanghai Research Institute of Acupuncture and Meridian, Shanghai, China (H.M.); and Respiratory Medicine Department, Central Hospital Affiliated to Shenyang Medical College, Liaoning, China (M.M., S.X.)
| | - Mingqing Mao
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (X.Z., Q.P., H.W., X.Q., P.S., L.Z., G.G., L.Y.); Center for Systems Pharmacokinetics, Shanghai University of Traditional Chinese Medicine, Shanghai, China (X.Z., Q.P., H.W., X.Q., P.S., L.Z., G.G., L.Y.); College of Basic Medical Sciences, Dalian Medical University, Liaoning, China (H.M.); Shanghai Research Institute of Acupuncture and Meridian, Shanghai, China (H.M.); and Respiratory Medicine Department, Central Hospital Affiliated to Shenyang Medical College, Liaoning, China (M.M., S.X.)
| | - Shuyue Xia
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (X.Z., Q.P., H.W., X.Q., P.S., L.Z., G.G., L.Y.); Center for Systems Pharmacokinetics, Shanghai University of Traditional Chinese Medicine, Shanghai, China (X.Z., Q.P., H.W., X.Q., P.S., L.Z., G.G., L.Y.); College of Basic Medical Sciences, Dalian Medical University, Liaoning, China (H.M.); Shanghai Research Institute of Acupuncture and Meridian, Shanghai, China (H.M.); and Respiratory Medicine Department, Central Hospital Affiliated to Shenyang Medical College, Liaoning, China (M.M., S.X.)
| | - Guangbo Ge
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (X.Z., Q.P., H.W., X.Q., P.S., L.Z., G.G., L.Y.); Center for Systems Pharmacokinetics, Shanghai University of Traditional Chinese Medicine, Shanghai, China (X.Z., Q.P., H.W., X.Q., P.S., L.Z., G.G., L.Y.); College of Basic Medical Sciences, Dalian Medical University, Liaoning, China (H.M.); Shanghai Research Institute of Acupuncture and Meridian, Shanghai, China (H.M.); and Respiratory Medicine Department, Central Hospital Affiliated to Shenyang Medical College, Liaoning, China (M.M., S.X.)
| | - Ling Yang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China (X.Z., Q.P., H.W., X.Q., P.S., L.Z., G.G., L.Y.); Center for Systems Pharmacokinetics, Shanghai University of Traditional Chinese Medicine, Shanghai, China (X.Z., Q.P., H.W., X.Q., P.S., L.Z., G.G., L.Y.); College of Basic Medical Sciences, Dalian Medical University, Liaoning, China (H.M.); Shanghai Research Institute of Acupuncture and Meridian, Shanghai, China (H.M.); and Respiratory Medicine Department, Central Hospital Affiliated to Shenyang Medical College, Liaoning, China (M.M., S.X.)
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23
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Cazzola M, Matera MG. The effect of doxofylline in asthma and COPD. Respir Med 2020; 164:105904. [PMID: 32094104 DOI: 10.1016/j.rmed.2020.105904] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 02/17/2020] [Indexed: 10/25/2022]
Abstract
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.
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Affiliation(s)
- Mario Cazzola
- Chair of Respiratory Medicine, Department of Experimental Medicine, University of Rome Tor Vergata, Italy.
| | - Maria Gabriella Matera
- Chair of Pharmacology, Department of Experimental Medicine, University of Campania, Naples, Italy
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24
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Matera MG, Page CP, Calzetta L, Rogliani P, Cazzola M. Pharmacology and Therapeutics of Bronchodilators Revisited. Pharmacol Rev 2020; 72:218-252. [PMID: 31848208 DOI: 10.1124/pr.119.018150] [Citation(s) in RCA: 100] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Bronchodilators remain the cornerstone of the treatment of airway disorders such as asthma and chronic obstructive pulmonary disease (COPD). There is therefore considerable interest in understanding how to optimize the use of our existing classes of bronchodilator and in identifying novel classes of bronchodilator drugs. However, new classes of bronchodilator have proved challenging to develop because many of these have no better efficacy than existing classes of bronchodilator and often have unacceptable safety profiles. Recent research has shown that optimization of bronchodilation occurs when both arms of the autonomic nervous system are affected through antagonism of muscarinic receptors to reduce the influence of parasympathetic innervation of the lung and through stimulation of β 2-adrenoceptors (β 2-ARs) on airway smooth muscle with β 2-AR-selective agonists to mimic the sympathetic influence on the lung. This is currently achieved by use of fixed-dose combinations of inhaled long-acting β 2-adrenoceptor agonists (LABAs) and long-acting muscarinic acetylcholine receptor antagonists (LAMAs). Due to the distinct mechanisms of action of LAMAs and LABAs, the additive/synergistic effects of using these drug classes together has been extensively investigated. More recently, so-called "triple inhalers" containing fixed-dose combinations of both classes of bronchodilator (dual bronchodilation) and an inhaled corticosteroid in the same inhaler have been developed. Furthermore, a number of so-called "bifunctional drugs" having two different primary pharmacological actions in the same molecule are under development. This review discusses recent advancements in knowledge on bronchodilators and bifunctional drugs for the treatment of asthma and COPD. SIGNIFICANCE STATEMENT: Since our last review in 2012, there has been considerable research to identify novel classes of bronchodilator drugs, to further understand how to optimize the use of the existing classes of bronchodilator, and to better understand the role of bifunctional drugs in the treatment of asthma and chronic obstructive pulmonary disease.
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Affiliation(s)
- M G Matera
- Unit of Pharmacology, Department of Experimental Medicine, University of Campania "Luigi Vanvitelli," Naples, Italy (M.G.M.); Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, United Kingdom (C.P.P.); and Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata," Rome, Italy (L.C., P.R., M.C.)
| | - C P Page
- Unit of Pharmacology, Department of Experimental Medicine, University of Campania "Luigi Vanvitelli," Naples, Italy (M.G.M.); Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, United Kingdom (C.P.P.); and Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata," Rome, Italy (L.C., P.R., M.C.)
| | - L Calzetta
- Unit of Pharmacology, Department of Experimental Medicine, University of Campania "Luigi Vanvitelli," Naples, Italy (M.G.M.); Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, United Kingdom (C.P.P.); and Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata," Rome, Italy (L.C., P.R., M.C.)
| | - P Rogliani
- Unit of Pharmacology, Department of Experimental Medicine, University of Campania "Luigi Vanvitelli," Naples, Italy (M.G.M.); Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, United Kingdom (C.P.P.); and Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata," Rome, Italy (L.C., P.R., M.C.)
| | - M Cazzola
- Unit of Pharmacology, Department of Experimental Medicine, University of Campania "Luigi Vanvitelli," Naples, Italy (M.G.M.); Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, United Kingdom (C.P.P.); and Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata," Rome, Italy (L.C., P.R., M.C.)
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25
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Calzetta L, Matera MG, Goldstein MF, Fairweather WR, Howard WW, Cazzola M, Rogliani P. A long-term clinical trial on the efficacy and safety profile of doxofylline in Asthma: The LESDA study. Pulm Pharmacol Ther 2019; 60:101883. [PMID: 31884206 DOI: 10.1016/j.pupt.2019.101883] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 12/23/2019] [Accepted: 12/23/2019] [Indexed: 12/15/2022]
Abstract
Doxofylline, an oral methylxanthine with bronchodilator and anti-inflammatory activities, offers a promising alternative to theophylline due to its superior efficacy/safety profile. No long-term studies on the efficacy and safety of doxofylline are currently available in asthma. The aim of the Long-term clinical trial on the Efficacy and Safety profile of Doxofylline in Asthma (LESDA) study was to investigate the safety and efficacy profile of doxofylline administered for one year in asthmatic patients. LESDA was a multicenter, open-label, Phase III, clinical trial in which adult asthmatic patients received the same treatment (oral doxofylline 400 mg t.i.d.) for one year. Efficacy was assessed through periodic pulmonary function tests and by having the subjects keep monthly records of asthma events rates and use of salbutamol as rescue medication. The rate of adverse events (AEs) was recorded during the study. Three-hundred nine patients were screened and allocated in the study. Doxofylline significantly improved the change from baseline in forced expiratory volume in 1 s (FEV1) (+16.90 ± 1.81%, P < 0.001 vs. baseline). Doxofylline also significantly improved the rate of asthma events (events/day: -0.57 ± 0.18, P < 0.05 vs. baseline) and the use of salbutamol as rescue medication (puffs/day: -1.48 ± 0.25, P < 0.01 vs. baseline). The most common AEs were nausea (14.56%), headache (14.24%), insomnia (10.68%), and dyspepsia (10.03%). There were neither serious AEs nor deaths during or shortly after the study. Concluding, doxofylline is effective and well tolerated when administered chronically in asthmatic patients.
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Affiliation(s)
- Luigino Calzetta
- Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy.
| | - Maria Gabriella Matera
- Unit of Pharmacology, Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | | | | | | | - Mario Cazzola
- Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Paola Rogliani
- Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy
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Talmon M, Massara E, Brunini C, Fresu LG. Comparison of anti-inflammatory mechanisms between doxofylline and theophylline in human monocytes. Pulm Pharmacol Ther 2019; 59:101851. [PMID: 31563516 DOI: 10.1016/j.pupt.2019.101851] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 09/26/2019] [Accepted: 09/26/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND Methylxanthines are important pharmacological agents in the treatment of asthma and of chronic obstructive pulmonary diseases. The present study was designed to compare the ability of doxofylline and theophylline to modulate inflammatory pathways in human monocytes. METHODS Monocytes isolated from healthy anonymous human buffy coats were treated with doxofylline or theophylline in the presence of phorbol 12-myristate 13-acetate (PMA) or lipopolysaccharide (LPS), and their phenotype, the oxidative burst, cytokine expression and release, cAMP production, and protein kinase C (PKC) activity were evaluated. RESULTS Doxofylline and theophylline did not have overlapping effects on human monocytes. While sharing some common characteristics, they differed significantly in their selectivity. Theophylline affected LPS- above PMA-induced cellular responsivity, while doxofylline behaved in the opposite manner. Furthermore, when testing PKC activity, we found an inhibitory effect of doxofylline but not of theophylline, at equimolar doses. CONCLUSIONS In conclusion, our data support the growing hypothesis that doxofylline does not have a superimposable mechanism of action compared to theophylline, and this may both explain some differences in the risk/benefit ratio and may direct studies to tailor therapy for patients.
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Affiliation(s)
- Maria Talmon
- Department of Health Sciences, University of Piemonte Orientale, Via Solaroli 17, 28100, Novara, Italy
| | - Erika Massara
- Department of Health Sciences, University of Piemonte Orientale, Via Solaroli 17, 28100, Novara, Italy
| | - Chiara Brunini
- Department of Health Sciences, University of Piemonte Orientale, Via Solaroli 17, 28100, Novara, Italy
| | - Luigia Grazia Fresu
- Department of Health Sciences, University of Piemonte Orientale, Via Solaroli 17, 28100, Novara, Italy.
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Development and validation of a UPLC-MS/MS method for quantification of doxofylline and its metabolites in human plasma. J Pharm Biomed Anal 2019; 174:220-225. [DOI: 10.1016/j.jpba.2019.05.039] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Revised: 05/18/2019] [Accepted: 05/20/2019] [Indexed: 02/06/2023]
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Cazzola M, Rogliani P, Stolz D, Matera MG. Pharmacological treatment and current controversies in COPD. F1000Res 2019; 8:F1000 Faculty Rev-1533. [PMID: 31508197 PMCID: PMC6719668 DOI: 10.12688/f1000research.19811.1] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/20/2019] [Indexed: 12/16/2022] Open
Abstract
Bronchodilators, corticosteroids, and antibiotics are still key elements for treating chronic obstructive pulmonary disease in the 2019 Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommendations and this is due in part to our current inability to discover new drugs capable of decisively influencing the course of the disease. However, in recent years, information has been produced that, if used correctly, can allow us to improve the use of the available therapies.
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Affiliation(s)
- Mario Cazzola
- Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Paola Rogliani
- Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Daiana Stolz
- Clinic of Respiratory Medicine and Pulmonary Cell Research, University Hospital of Basel, Basel, Switzerland
| | - Maria Gabriella Matera
- Unit of Pharmacology, Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
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Rogliani P, Calzetta L, Ora J, Cazzola M, Matera MG. Efficacy and safety profile of doxofylline compared to theophylline in asthma: a meta-analysis. Multidiscip Respir Med 2019; 14:25. [PMID: 31388422 PMCID: PMC6679461 DOI: 10.1186/s40248-019-0189-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 05/29/2019] [Indexed: 01/17/2023] Open
Abstract
Background Oral methylxanthines are effective drugs for the treatment of chronic obstructive respiratory disorders. The novel methylxanthine doxofylline, that has bronchodilator and anti-inflammatory activities, is not affected by the major drawback of theophylline. Nowadays large-scale quantitative synthesis comparing the efficacy and safety profile of doxofylline vs. theophylline in the treatment of asthma is still lacking. Therefore, we performed a quantitative synthesis to compare the efficacy/safety profile of doxofylline and theophylline in asthma. Methods A pairwise and network meta-analyses were performed to assess the impact of doxofylline vs. theophylline and placebo on the change in asthma events, risk of adverse events (AEs), forced expiratory volume in 1 s (FEV1), and salbutamol use. Results Data obtained from 696 asthmatic patients were extracted from 4 randomized controlled trials published between 2015 and 2018. Doxofylline was significantly (P < 0.05) more effective than theophylline in reducing the daily asthma events (mean difference − 0.14, 95%CI -0.27 – 0.00) and risk of AEs (relative risk 0.76, 95%CI 0.59–0.99). Doxofylline was as effective as theophylline in improving FEV1, and a trend of superiority (P = 0.058) was detected for doxofylline over theophylline with respect to the reduction in the use of salbutamol as rescue medication. The rank of effectiveness was doxofylline>theophylline> > placebo, and the rank of safety was placebo>doxofylline> > theophylline. Conclusions Doxofylline is an effective and safe methylxanthine for the treatment of asthma, with an efficacy/safety profile greater than that of theophylline. Trial registration Meta-analysis registration: CRD42019119849.
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Affiliation(s)
- Paola Rogliani
- 1Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy
| | - Luigino Calzetta
- 1Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy
| | - Josuel Ora
- 2Division of Respiratory Medicine, University Hospital "Tor Vergata", Rome, Italy
| | - Mario Cazzola
- 1Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy
| | - Maria Gabriella Matera
- 3Unit of Pharmacology, Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
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Ti H, Zhou Y, Liang X, Li R, Ding K, Zhao X. Targeted Treatments for Chronic Obstructive Pulmonary Disease (COPD) Using Low-Molecular-Weight Drugs (LMWDs). J Med Chem 2019; 62:5944-5978. [PMID: 30682248 DOI: 10.1021/acs.jmedchem.8b01520] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Chronic obstructive pulmonary disease (COPD) is a very common and frequently fatal airway disease. Current therapies for COPD depend mainly on long-acting bronchodilators, which cannot target the pathogenic mechanisms of chronic inflammation in COPD. New pharmaceutical therapies for the inflammatory processes of COPD are urgently needed. Several anti-inflammatory targets have been identified based on increased understanding of the pathogenesis of COPD, which raises new hopes for targeted treatment of this fatal respiratory disease. In this review, we discuss the recent advances in bioactive low-molecular-weight drugs (LMWDs) for the treatment of COPD and, in addition to the first-line drug bronchodilators, focus particularly on low-molecular-weight anti-inflammatory agents, including modulators of inflammatory mediators, inflammasome inhibitors, protease inhibitors, antioxidants, PDE4 inhibitors, kinase inhibitors, and other agents. We also provide new insights into targeted COPD treatments using LMWDs, particularly small-molecule agents.
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Affiliation(s)
- Huihui Ti
- Key Laboratory of Molecular Target & Clinical Pharmacology, State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital , Guangzhou Medical University , Guangzhou 511436 , P. R. China
| | - Yang Zhou
- Key Laboratory of Molecular Target & Clinical Pharmacology, State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital , Guangzhou Medical University , Guangzhou 511436 , P. R. China.,Division of Theoretical Chemistry and Biology, School of Biotechnology , Royal Institute of Technology (KTH) , AlbaNova University Center , Stockholm SE-100 44 , Sweden
| | - Xue Liang
- Key Laboratory of Molecular Target & Clinical Pharmacology, State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital , Guangzhou Medical University , Guangzhou 511436 , P. R. China
| | - Runfeng Li
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital , Guangzhou Medical University , Guangzhou 510120 , P. R. China
| | - Ke Ding
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy , Jinan University , Guangzhou 510632 , P. R. China.,State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital , Guangzhou Medical University , Guangzhou 510120 , P. R. China
| | - Xin Zhao
- Key Laboratory of Molecular Target & Clinical Pharmacology, State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital , Guangzhou Medical University , Guangzhou 511436 , P. R. China.,School of Life Sciences , The Chinese University of Hong Kong , Shatin, N.T. , Hong Kong SAR 999077 , P. R. China
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Ntontsi P, Detta A, Bakakos P, Loukides S, Hillas G. Experimental and investigational phosphodiesterase inhibitors in development for asthma. Expert Opin Investig Drugs 2019; 28:261-266. [PMID: 30678501 DOI: 10.1080/13543784.2019.1571582] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
INTRODUCTION Severe, inadequately-controlled asthma remains a clinical challenge. For this reason, clinical trials and preclinical experimental studies on novel agents as an add-on therapies continue emerge. Phosphodiesterases (PDEs) are enzymes that regulate the function of immune cells by hydrolyzing cyclic guanosine monophosphate/cGMP and cyclic adenosine monophosphate/cAMP. PDEs are divided into subfamilies [PDE3, PDE4, PDE5 and PDE7] which are mainly found in the respiratory tract. Inhibitors of PDEs have already been approved for COPD and pulmonary hypertension. AREAS COVERED The role of PDE inhibitors in asthma treatment and the possible mechanism of action via their anti-inflammatory and/or bronchodilating effect are discussed. EXPERT OPINION Novel PDE inhibitors exhibiting fewer adverse events may have a role as add-on therapies in asthma treatment in the future. More clinical trials are necessary to prove their efficacy and evaluate their safety profile before approval by regulatory bodies is granted.
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Affiliation(s)
- Polyxeni Ntontsi
- a 2nd Respiratory Medicine Department , National and Kapodistrian University of Athens, Medical School, Attikon Hospital , Athens , Greece
| | - Aggeliki Detta
- b 1st Respiratory Medicine Department , National and Kapodistrian University of Athens, Medical School, Sotiria Chest Hospital , Athens , Greece
| | - Petros Bakakos
- b 1st Respiratory Medicine Department , National and Kapodistrian University of Athens, Medical School, Sotiria Chest Hospital , Athens , Greece
| | - Stelios Loukides
- a 2nd Respiratory Medicine Department , National and Kapodistrian University of Athens, Medical School, Attikon Hospital , Athens , Greece
| | - Georgios Hillas
- c 5th Pulmonary Department , "Sotiria" Chest Diseases Hospital , Athens , Greece
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Calzetta L, Hanania NA, Dini FL, Goldstein MF, Fairweather WR, Howard WW, Cazzola M. Impact of doxofylline compared to theophylline in asthma: A pooled analysis of functional and clinical outcomes from two multicentre, double-blind, randomized studies (DOROTHEO 1 and DOROTHEO 2). Pulm Pharmacol Ther 2018; 53:20-26. [PMID: 30219705 DOI: 10.1016/j.pupt.2018.09.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 09/10/2018] [Accepted: 09/12/2018] [Indexed: 12/26/2022]
Abstract
This pooled analysis of double-blind, randomized, placebo-controlled trials aimed to investigate the impact of DOxofylline compaRed tO THEOphylline (DOROTHEO 1 and DOROTHEO 2 studies) on functional and clinical outcomes in asthma. Asthmatic patients ≥16 years of age with forced expiratory volume in 1 s (FEV1) ≥50% and <80% and with ≥15% post-bronchodilator increase in FEV1 were randomized in a 1:1:1:1 ratio in DOROTHEO 1 to receive doxofylline 200 mg, doxofylline 400 mg, theophylline 250 mg, or placebo; in DOROTHEO 2 patients were randomized in a 1:1:1 ratio to receive doxofylline 400 mg, theophylline 250 mg, or placebo. All double-blind treatments were taken orally with immediate release formulations and three times daily. Data evaluating the effect of doxofylline 400 mg, theophylline 250 mg and placebo on FEV1, asthma events rate, use of salbutamol as rescue medication and adverse events (AEs) were pooled from both studies. The pooled-analysis of 483 patients demonstrated that both doxofylline 400 mg and theophylline 250 mg significantly increased FEV1, reduced the rate of asthma events and use of salbutamol to relieve asthma symptoms compared to placebo (p < 0.01). No significant differences were detected between doxofylline 400 mg and theophylline 250 mg. Doxofylline 400 mg did not significantly (p > 0.05) increase the risk of AEs compared to placebo, conversely in patients treated with theophylline 250 mg the risk of AEs was significantly (p < 0.05) greater than in those that received placebo. We conclude that doxofylline seems to offer a promising alternative to theophylline with a superior efficacy/safety profile in the management of patients with asthma.
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Affiliation(s)
- Luigino Calzetta
- Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome, Italy
| | - Nicola A Hanania
- Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Frank L Dini
- Cardiopulmonary and Vascular Department, University of Pisa, Pisa, Italy
| | | | | | | | - Mario Cazzola
- Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome, Italy.
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Willson C. The clinical toxicology of caffeine: A review and case study. Toxicol Rep 2018; 5:1140-1152. [PMID: 30505695 PMCID: PMC6247400 DOI: 10.1016/j.toxrep.2018.11.002] [Citation(s) in RCA: 123] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2018] [Revised: 10/09/2018] [Accepted: 11/01/2018] [Indexed: 02/08/2023] Open
Abstract
Caffeine is a widely recognized psychostimulant compound with a long history of consumption by humans. While it has received a significant amount of attention there is still much to be learned with respect to its toxicology in humans, especially in cases of overdose. A review of the history of consumption and the clinical toxicology of caffeine including clinical features, pharmacokinetics, toxicokinetics, a thorough examination of mechanism of action and management/treatment strategies are undertaken. While higher (i.e., several grams) quantities of caffeine are known to cause toxicity and potentially lethality, cases of mainly younger individuals who have experienced severe side effects and death despite consuming doses not otherwise known to cause such harm is troubling and deserves further study. An attempted case reconstruction is performed in an effort to shed light on this issue with a focus on the pharmacokinetics and pharmacodynamics of caffeine.
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Matera MG, Rinaldi B, Page C, Rogliani P, Cazzola M. Pharmacokinetic considerations concerning the use of bronchodilators in the treatment of chronic obstructive pulmonary disease. Expert Opin Drug Metab Toxicol 2018; 14:1101-1111. [DOI: 10.1080/17425255.2018.1530215] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Affiliation(s)
- Maria Gabriella Matera
- Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Barbara Rinaldi
- Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Clive Page
- Sackler Institute of Pulmonary Pharmacology, King’s College London, London, UK
| | - Paola Rogliani
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy
| | - Mario Cazzola
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy
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35
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Cazzola M, Calzetta L, Barnes PJ, Criner GJ, Martinez FJ, Papi A, Gabriella Matera M. Efficacy and safety profile of xanthines in COPD: a network meta-analysis. Eur Respir Rev 2018; 27:27/148/180010. [PMID: 29720510 DOI: 10.1183/16000617.0010-2018] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Accepted: 03/11/2018] [Indexed: 12/23/2022] Open
Abstract
Theophylline can still have a role in the management of stable chronic obstructive pulmonary disease (COPD), but its use remains controversial, mainly due to its narrow therapeutic window. Doxofylline, another xanthine, is an effective bronchodilator and displays a better safety profile than theophylline. Therefore, we performed a quantitative synthesis to compare the efficacy and safety profile of different xanthines in COPD.The primary end-point of this meta-analysis was the impact of xanthines on lung function. In addition, we assessed the risk of adverse events by normalising data on safety as a function of person-weeks. Data obtained from 998 COPD patients were selected from 14 studies and meta-analysed using a network approach.The combined surface under the cumulative ranking curve (SUCRA) analysis of efficacy (change from baseline in forced expiratory volume in 1 s) and safety (risk of adverse events) showed that doxofylline was superior to aminophylline (comparable efficacy and significantly better safety), bamiphylline (significantly better efficacy and comparable safety), and theophylline (comparable efficacy and significantly better safety).Considering the overall efficacy/safety profile of the investigated agents, the results of this quantitative synthesis suggest that doxofylline seems to be the best xanthine for the treatment of COPD.
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Affiliation(s)
- Mario Cazzola
- Dept of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy
| | - Luigino Calzetta
- Dept of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy
| | - Peter J Barnes
- Airway Disease Section, National Heart and Lung Institute, Imperial College, London, UK
| | - Gerard J Criner
- Dept of Thoracic Medicine and Surgery, Temple Lung Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - Fernando J Martinez
- Joan and Sanford I. Weill Dept of Medicine, Weill Cornell Medical College, New York - Presbyterian Hospital/Weill Cornell Medical Center, New York, NY, USA
| | - Alberto Papi
- Dept of Internal and Cardiorespiratory Medicine, Research Center on Asthma and COPD, University of Ferrara, Ferrara, Italy
| | - Maria Gabriella Matera
- Dept of Experimental Medicine, Unit of Pharmacology, University of Campania Luigi Vanvitelli, Naples, Italy
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Cazzola M, Calzetta L, Rogliani P, Page C, Matera MG. Impact of doxofylline in COPD: A pairwise meta-analysis. Pulm Pharmacol Ther 2018; 51:1-9. [PMID: 29705620 DOI: 10.1016/j.pupt.2018.04.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 04/24/2018] [Indexed: 02/07/2023]
Abstract
Doxofylline is an effective bronchodilator for relieving airway obstruction in patients with asthma or chronic obstructive pulmonary disease (COPD), and displays a better safety profile with respect to theophylline. Herein, we performed a pairwise meta-analysis of the currently available data to provide consistent and homogeneous findings on the impact of this xanthine in COPD patients. Results obtained from 820 patients were selected from 20 clinical trials. Meta-regression was performed to examine the source of heterogeneity between-studies and identify potential confounder covariates. The quality of the evidence was assessed by the GRADE system. Doxofylline induced a significant (P < 0.001) increase in forced expiratory volume in 1 s (FEV1) of 8.20% (95%CI 4.00-12.41; I2 93%) and 317 ml (95%CI 19-439; I2 87%) compared with baseline. The total administered dose of doxofylline significantly (P < 0.001) interacted with the size of the effect estimates detected for FEV1. Doxofylline induced a significant (P < 0.001), although moderate, increase in adverse events (AEs) frequency (proportion 0.03, 95%CI 0.02-0.04; I2 88%), but only epigastralgia, nausea, dyspepsia and headache were statistically significant (P < 0.05). The GRADE analysis indicated high quality of evidence (++++) for the impact of doxofylline on FEV1, and moderate quality of evidence (+++) for the safety profile in COPD patients. Doxofylline is an effective and safe medicine when administered to patients with COPD and can be considered as an alternative to theophylline.
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Affiliation(s)
- Mario Cazzola
- Unit of Respiratory Medicine, Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome, Italy
| | - Luigino Calzetta
- Unit of Respiratory Medicine, Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome, Italy.
| | - Paola Rogliani
- Unit of Respiratory Medicine, Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome, Italy
| | - Clive Page
- Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, UK
| | - Maria Gabriella Matera
- Unit of Pharmacology, Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
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Gross N. The COPD Pipeline XXXVIII. CHRONIC OBSTRUCTIVE PULMONARY DISEASES-JOURNAL OF THE COPD FOUNDATION 2018; 5:144-147. [PMID: 30374452 DOI: 10.15326/jcopdf.5.2.2018.0136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Affiliation(s)
- Nicholas Gross
- St Francis Hospital and University Medical Research, LLC
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38
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Mokry J, Urbanova A, Kertys M, Mokra D. Inhibitors of phosphodiesterases in the treatment of cough. Respir Physiol Neurobiol 2018; 257:107-114. [PMID: 29337269 DOI: 10.1016/j.resp.2018.01.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 12/28/2017] [Accepted: 01/11/2018] [Indexed: 02/08/2023]
Abstract
A group of 11 enzyme families of metalophosphohydrolases called phosphodiesterases (PDEs) is responsible for a hydrolysis of intracellular cAMP and cGMP. Xanthine derivatives (methylxanthines) inhibit PDEs without selective action on their single isoforms and lead to many pharmacological effects, e.g. bronchodilation, anti-inflammatory and immunomodulating effects, and thus they can modulate the cough reflex. Contrary, selective PDE inhibitors have been developed to inhibit PDE isoforms with different pharmacological effects based on their tissue expression. In this paper, effects of non-selective PDE inhibitors (e.g. theophylline) are discussed, with a description of other putative mechanisms in their effects on cough. Antitussive effects of selective inhibitors of several PDE isoforms are reviewed, focusing on PDE1, PDE3, PDE4, PDE5 and PDE7. The inhibition of PDEs suggests participation of bronchodilation, suppression of TRPV channels and anti-inflammatory action in cough suppression. Selective PDE3, PDE4 and PDE5 inhibitors have demonstrated the most significant cough suppressive effects, confirming their benefits in chronic inflammatory airway diseases associated with bronchoconstriction and cough.
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Affiliation(s)
- Juraj Mokry
- Department of Pharmacology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia; Biomedical Center Martin (BioMed), Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia.
| | - Anna Urbanova
- Department of Pharmacology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia; Biomedical Center Martin (BioMed), Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - Martin Kertys
- Department of Pharmacology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia; Biomedical Center Martin (BioMed), Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - Daniela Mokra
- Biomedical Center Martin (BioMed), Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia; Department of Physiology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
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