Clarithromycin, trimethoprim, and penicillin and oxidative nucleic acid modifications in humans: randomised, controlled trials

Larsen, Emil List; Cejvanovic, Vanja; Kjær, Laura Kofoed; Pedersen, Morten Thorup; Popik, Sara Daugaard; Hansen, Lina Kallehave; Andersen, Jón Trærup; Jimenez-Solem, Espen; Broedbaek, Kasper; Petersen, Morten Aagaard; Weimann, Allan; Henriksen, Trine; Lykkesfeldt, Jens; Torp‐Pedersen, Christian; Poulsen, Henrik E.

doi:10.1111/bcp.13261

Cited by 9 publications

(3 citation statements)

References 51 publications

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“…In the CLARICOR study two wks. of clarithromycin treatment, in individuals with ischemic heart disease, increased long-term mortality primarily due to increased cardiovascular mortality [35], possibly due to increased oxidatively generated damage [36]. Indeed, in a RCT, one week of clarithromycin treatment resulted in increases of 22% in urinary 8-oxodG levels and 15% in urinary 8-oxoGuo levels [36].…”

Section: Discussionmentioning

confidence: 99%

“…of clarithromycin treatment, in individuals with ischemic heart disease, increased long-term mortality primarily due to increased cardiovascular mortality [35], possibly due to increased oxidatively generated damage [36]. Indeed, in a RCT, one week of clarithromycin treatment resulted in increases of 22% in urinary 8-oxodG levels and 15% in urinary 8-oxoGuo levels [36]. In later subgroup analysis of the CLARICOR study the negative effect was attenuated in individuals receiving statin at baseline, implying a protective effect of statins [37].…”

Section: Discussionmentioning

confidence: 99%

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Statin treatment, oxidative stress and inflammation in a Danish population

et al. 2019

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Background While statins may have anti-inflammatory effects, anti-oxidative effects are controversial. We investigated if statin treatment is associated with differences in oxidatively generated nucleotide damage and chronic inflammation, and the relationship between nucleotide damage and chronic inflammation. Methods We included 19,795 participants from the Danish General Suburban Population Study. In 3420 participants, we measured urinary 8-oxodG and 8-oxoGuo by liquid chromatography-tandem mass spectrometry as markers of oxidatively generated damage to DNA and RNA, respectively. We used a composite score for chronic inflammation (INFLA score) of hsCRP, WBC, platelet count, and neutrophil granulocyte to lymphocyte ratio. Associations were assessed using multivariate linear regression models. Results Compared with non-users, statin users had 4.3–6.0% lower 8-oxodG in three separate models ( p < 0.05); there were no differences in 8-oxoGuo. Among participants aged > 60 y, statin users had 11.4% lower 8-oxodG (95%CI: 6.7–15.9%, p interaction <0.001) and 3.9% lower 8-oxoGuo (95%CI: 0.1–7.5%, p interaction = 0.002), compared with non-users. Compared with non-users, statin users had 11.1% (95%CI: 5.4–16.5%, p interaction <0.001) lower 8-oxodG in participants treated for hypertension, and 18.6% (95%CI: 6.8–28.9%, p interaction <0.001) lower 8-oxodG in participants with decreased renal function. Compared with non-users, statin users had significantly lower INFLA score ( p < 0.001). 8-oxodG and 8-oxoGuo associated positively with markers of chronic inflammation. Conclusions Oxidatively generated DNA damage and inflammatory burden are lower in statin users compared with non-users. Together, anti-oxidative and anti-inflammatory effects may contribute to the beneficial effects of statins.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Statin treatment, oxidative stress and inflammation in a Danish population

et al. 2019

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“…Values of the primary outcomes are about 30 nmol with SD of 6 nmol per 24 hour based on baseline values from the PENTRIOX trial. 36 Smoking increases urinary excretion of 8-oxodG by 50% (95% CI 31% to 69%). 37 We wish to be able to detect an effect size of 20%, since we do not believe smaller changes are clinically relevant.…”

Section: Methods and Analysismentioning

confidence: 98%

The effect of empagliflozin on oxidative nucleic acid modifications in patients with type 2 diabetes: protocol for a randomised, double-blinded, placebo-controlled trial

et al. 2017

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IntroductionCardiovascular disease is the leading cause of morbidity and mortality in patients with type 2 diabetes (T2D). Although glycaemic control reduces microvascular complications, the effect of intensive treatment strategies or individual drugs on macrovascular diseases is still debated. RNA oxidation is associated with increased mortality in patients with T2D. Inspired by animal studies showing effect of a sodium-glucose cotransporter-2 (SGLT-2) inhibitor (empagliflozin) on oxidative stress and a recent trial evaluating empagliflozin that demonstrated improved cardiovascular outcomes in patients with T2D at high risk of cardiovascular events, we hypothesise that empagliflozin lowers oxidative stress.Methods and analysisIn this randomised, double-blinded and placebo-controlled study, 34 adult males with T2D will be randomised (1:1) to empagliflozin or placebo once daily for 14 days as add-on to ongoing therapy. The primary endpoints will be changes in 24-hour urinary excretion of 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2’-deoxyguanosine (8-oxodG) determined before and after intervention (by ultra-performance liquid chromatography tandem mass-spectrometry). Additionally, fasting levels of malondialdehyde (MDA) will be determined in plasma before and after intervention (by high-performance liquid chromatography). Further, the plasma levels of iron, transferrin, transferrin-saturation, and ferritin are determined to correlate the iron metabolism to the markers of oxidative modifications.Ethics and disseminationThe study protocol has been approved by the Regional Committee on Biomedical Research Ethics (approval number H-16017433), the Danish Medicines Agency, and the Danish Data Protection Agency, and will be carried out under the surveillance and guidance of the GCP unit at Bispebjerg Frederiksberg Hospital, University of Copenhagen in compliance with the ICH-GCP guidelines and in accordance with the Declaration of Helsinki. The results of this study will be presented at national and international conferences, and submitted to a peer-reviewed international journal with authorship in accordance with Internation Committee of Medical Journal Editors (ICMJE) Recommendations state.Trial registrationStudy name: EMPOX; Pre-results: clinicaltrials.gov (NCT02890745). Protocol version 5.1 - August, 2016.

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