Effect of doxycyline in chronic obstructive pulmonary disease - An exploratory study

Singh, Brajesh Kumar; Ghosh, Nilanjana; Saha, Debasri; Sarkar, Sailendra Nath; Bhattacharyya, Parthasarathi; Chaudhury, Koel

doi:10.1016/j.pupt.2019.101831

Cited by 14 publications

(19 citation statements)

References 65 publications

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“…Doxycycline ameliorated pulmonary inflammation in a murine polymicrobial sepsis model by decreasing levels of IL-1β, IL-6 and TNFα in plasma and lungs [54]. Doxycycline improved the lung function and quality of life in chronic obstructive pulmonary disease (COPD) [57]. Levels of IL-6, IL-8 and TNFα were reduced in doxycycline-treated COPD patients.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Antiviral Activity of Doxycycline against SARS-CoV-2

et al. 2020

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In December 2019, a new severe acute respiratory syndrome coronavirus (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19), emerged in Wuhan, China. Despite containment measures, SARS-CoV-2 spread in Asia, Southern Europe, then in America and currently in Africa. Identifying effective antiviral drugs is urgently needed. An efficient approach to drug discovery is to evaluate whether existing approved drugs can be efficient against SARS-CoV-2. Doxycycline, which is a second-generation tetracycline with broad-spectrum antimicrobial, antimalarial and anti-inflammatory activities, showed in vitro activity on Vero E6 cells infected with a clinically isolated SARS-CoV-2 strain (IHUMI-3) with median effective concentration (EC50) of 4.5 ± 2.9 µM, compatible with oral uptake and intravenous administrations. Doxycycline interacted both on SARS-CoV-2 entry and in replication after virus entry. Besides its in vitro antiviral activity against SARS-CoV-2, doxycycline has anti-inflammatory effects by decreasing the expression of various pro-inflammatory cytokines and could prevent co-infections and superinfections due to broad-spectrum antimicrobial activity. Therefore, doxycycline could be a potential partner of COVID-19 therapies. However, these results must be taken with caution regarding the potential use in SARS-CoV-2-infected patients: it is difficult to translate in vitro study results to actual clinical treatment in patients. In vivo evaluation in animal experimental models is required to confirm the antiviral effects of doxycycline on SARS-CoV-2 and more trials of high-risk patients with moderate to severe COVID-19 infections must be initiated.

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Section: Discussionmentioning

confidence: 99%

In Vitro Antiviral Activity of Doxycycline against SARS-CoV-2

et al. 2020

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“…Doxycycline was proposed to have several beneficial effects in patients with COPD and cystic fibrosis when used for the treatment of exacerbations (17,18). As described above, doxycycline could inhibit MMP activity and subsequently decrease MMP expression in several animal models and human studies.…”

Section: Discussionmentioning

confidence: 99%

“…Doxycycline is a broad-spectrum antibiotic belonging to the tetracycline family that is used to treat respiratory infections (15) and exacerbations in patients suffering from COPD or cystic fibrosis (16,17). Furthermore, doxycycline is suggested to have antioxidant and antiinflammatory properties that might be independent of MMP inhibition (18). Beneficial effects of doxycycline, mainly through MMP inhibition, have been reported in a number of preclinical studies (14,16,(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33).…”

Section: Introductionmentioning

confidence: 99%

The effect of long-term doxycycline treatment in a mouse model of cigarette smoke-induced emphysema and pulmonary hypertension

Hadžić

Gredic

et al. 2021

American Journal of Physiology-Lung Cellular and Molecular Phys

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Chronic obstructive pulmonary disease (COPD) is a major cause of death and a still incurable disease, comprising emphysema and chronic bronchitis. In addition to airflow limitation, COPD patients can suffer from pulmonary hypertension (PH). Doxycycline, an antibiotic from the tetracycline family, in addition to its pronounced antimicrobial activity, acts as a matrix metalloproteinase (MMP) inhibitor and has anti-inflammatory properties. Furthermore, doxycycline treatment exhibited a beneficial effect in several preclinical cardiovascular disease models. In preclinical research, doxycycline is frequently employed for gene expression modulation in Tet-On/Tet-Off transgenic animal models. Therefore, it is crucial to know whether doxycycline treatment in Tet-On/Tet-Off systems has effects independent of gene expression modulation by such systems. Against this background, we assessed the possible curative effects of long-term doxycycline administration in a mouse model of chronic CS exposure. Animals were exposed to CS for 8 months and then subsequently treated with doxycycline for additional 3 months in room-air conditions. Doxycycline decreased the expression of MMPs and general pro-inflammatory markers in the lungs from CS-exposed mice. This downregulation was, however, insufficient to ameliorate CS-induced emphysema or PH. Tet-On/Tet-Off induction by doxycycline in such models is a feasible genetic approach to study curative effects at least in established CS-induced emphysema and PH. However, we report several parameters that are influenced by doxycycline, and use of a Tet-On/Tet-Off system when evaluating those parameters should be interpreted with caution.

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“…Doxycycline reduced MMP concentrations in patients with CF, COPD, and tuberculosis chronic wounds, abdominal aortic aneurysm, and ophthalmological diseases [116][117][118][119][120][121][122][123][124][125][126][127][128][129][130][131][132][133][134] Anti-neoplastic effects (S2, S3, S50-S56, S62) Commercially available for treatment of rosacea and periodontal diseases [136][137][138][139][140][141][142] Recovery of patients was associated with a decrease in MMP concentrations as a consequence of treatment of orthopaedic indications with ß-lactams [111,112] and daptomycin [113], respiratory infections with macrolides [114,115] Evidence confirming a clinical benefit resulting from MMP-inhibition in patients is lacking for the remaining agents ion in the homologous active centre of the carbonic anhydrase [153,154] pH regulation, HC0…”

Section: S110)mentioning

confidence: 95%

“…Few investigators only have analysed enzyme activities or gene expression, whereas MMP concentrations in supernatants of cell cultures have been analysed in most of the studies. A decrease in MMP concentrations as a consequence of antibiotic treatment could be demonstrated in patients with orthopaedic infections treated with ß-lactams [111,112] and daptomycin [113], as well as pulmonary diseases treated with clarithromycin and azithromycin [114,115]; doxycycline reduced MMP concentrations in patients with CF, COPD, and tuberculosis [116][117][118][119], chronic wounds [120][121][122][123][124][125][126][127][128], abdominal aortic aneurysm [129][130][131][132], ophthalmological diseases [133,134], and in patients with acute lung injury following cardiac bypass [135]. Marketing authorizations have been granted for treatment of rosacea and periodontal diseases with sub-antimicrobial doses of doxycycline due to MMP inhibition [136][137][138][139][140][141][142].…”

Section: Antibiotics Inhibit Metallo-matrix-proteinasesmentioning

confidence: 99%

Selective toxicity of antibacterial agents—still a valid concept or do we miss chances and ignore risks?

Dalhoff

2020

Infection

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Background Selective toxicity antibacteribiotics is considered to be due to interactions with targets either being unique to bacteria or being characterized by a dichotomy between pro- and eukaryotic pathways with high affinities of agents to bacterial- rather than eukaryotic targets. However, the theory of selective toxicity oversimplifies the complex modes of action of antibiotics in pro- and eukaryotes. Methods and objective This review summarizes data describing multiple modes of action of antibiotics in eukaryotes. Results Aminoglycosides, macrolides, oxazolidinones, chloramphenicol, clindamycin, tetracyclines, glycylcyclines, fluoroquinolones, rifampicin, bedaquillin, ß-lactams inhibited mitochondrial translation either due to binding to mitosomes, inhibition of mitochondrial RNA-polymerase-, topoisomerase 2ß-, ATP-synthesis, transporter activities. Oxazolidinones, tetracyclines, vancomycin, ß-lactams, bacitracin, isoniazid, nitroxoline inhibited matrix-metalloproteinases (MMP) due to chelation with zinc and calcium, whereas fluoroquinols fluoroquinolones and chloramphenicol chelated with these cations, too, but increased MMP activities. MMP-inhibition supported clinical efficacies of ß-lactams and daptomycin in skin-infections, and of macrolides, tetracyclines in respiratory-diseases. Chelation may have contributed to neuroprotection by ß-lactams and fluoroquinolones. Aminoglycosides, macrolides, chloramphenicol, oxazolidins oxazolidinones, tetracyclines caused read-through of premature stop codons. Several additional targets for antibiotics in human cells have been identified like interaction of fluoroquinolones with DNA damage repair in eukaryotes, or inhibition of mucin overproduction by oxazolidinones. Conclusion The effects of antibiotics on eukaryotes are due to identical mechanisms as their antibacterial activities because of structural and functional homologies of pro- and eukaryotic targets, so that the effects of antibiotics on mammals are integral parts of their overall mechanisms of action.

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Effect of doxycyline in chronic obstructive pulmonary disease - An exploratory study

Cited by 14 publications

References 65 publications

In Vitro Antiviral Activity of Doxycycline against SARS-CoV-2

In Vitro Antiviral Activity of Doxycycline against SARS-CoV-2

The effect of long-term doxycycline treatment in a mouse model of cigarette smoke-induced emphysema and pulmonary hypertension

Selective toxicity of antibacterial agents—still a valid concept or do we miss chances and ignore risks?

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