Aldosterone glucuronidation inhibition as a potential mechanism for arterial dysfunction associated with chronic celecoxib and diclofenac use in patients with rheumatoid arthritis

M. A. Crilly*, A. A. Mangoni, K. M. Knights

*Corresponding author for this work

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Objective

Adverse cardiovascular (CV) effects of non-steroidal anti-inflammatory drugs (NSAIDs) are largely independent of their cyclooxygenase (COX) enzyme selectivity, but could be a consequence of aldosterone 18 beta-glucuronidation inhibition (AGI), which varies between NSAIDS. This study assesses the chronic effects of celecoxib (selective COX-2 inhibitor) versus diclofenac (non-selective NSAID) therapy on arterial dysfunction in patients with rheumatoid arthritis (RA).

Methods

AGI was assessed in vitro using human kidney cortical microsomes. Arterial function was measured clinically as the extent (augmentation index, AIX%) and timing (reflected wave transit time, RWTT, msec) of arterial wave reflection using radial applanation pulse wave analysis (SphygmoCor PWA device) in 39 RA patients without overt CV disease aged 40-65. A higher AIX% (and lower RWTT) indicates arterial dysfunction. Clinical assessment on a single occasion included a fasting blood sample, patient questionnaire and medical record review. Multivariable analysis was used to adjust for sex, mean blood pressure, arthritis duration, cumulative ESR-years and current DMARD therapy.

Results

The inhibition constant (K-i) for celecoxib was lower than that of diclofenac (K-i 3.5 vs. 8.4 mu M). Chronic celecoxib use was associated with a higher AIX% (34.8 vs. 32.3) and lower RWTT (130.1 vs. 132.7 msec) compared with diclofenac. Adjusted mean differences were AIX% 4.7 (95%CI 0.6 to 8.9; p=0.03) and RWTT -3.6 (95%CI-10.0 to 2.7; p=0.26).

Conclusion

Celecoxib has a greater potency for AGI than diclofenac and its use is associated with a significantly higher AIX%. Our findings support AGI as a plausible mechanism for the CV toxicity of NSAIDs.

Original languageEnglish
Pages (from-to)691-698
Number of pages8
JournalClinical and Experimental Rheumatology
Volume31
Issue number5
Early online date31 Jul 2013
Publication statusPublished - Sep 2013

Fingerprint

Celecoxib
Diclofenac
Aldosterone
Rheumatoid Arthritis
Anti-Inflammatory Agents
Pulse Wave Analysis
Antirheumatic Agents
Cyclooxygenase 2 Inhibitors
Prostaglandin-Endoperoxide Synthases
Microsomes
Pharmaceutical Preparations
Arthritis
Medical Records
Fasting
Cardiovascular Diseases
Blood Pressure
Kidney
Drug Therapy
Equipment and Supplies
Inhibition (Psychology)

Keywords

  • rheumatoid arthritis
  • non-steroidal anti-inflammatory drugs
  • aldosterone
  • arterial dysfunction
  • pulse wave analysis
  • nonsteroidal antiinflammatory drugs
  • pulse-wave analysis
  • blood-pressure
  • cardiovascular mortality
  • augmentation index
  • stiffness
  • risk
  • metaanalysis
  • cyclo-oxygenase-2
  • cyclooxygenase

Cite this

@article{4f449d3128b44924b31ef44bd79800ca,
title = "Aldosterone glucuronidation inhibition as a potential mechanism for arterial dysfunction associated with chronic celecoxib and diclofenac use in patients with rheumatoid arthritis",
abstract = "ObjectiveAdverse cardiovascular (CV) effects of non-steroidal anti-inflammatory drugs (NSAIDs) are largely independent of their cyclooxygenase (COX) enzyme selectivity, but could be a consequence of aldosterone 18 beta-glucuronidation inhibition (AGI), which varies between NSAIDS. This study assesses the chronic effects of celecoxib (selective COX-2 inhibitor) versus diclofenac (non-selective NSAID) therapy on arterial dysfunction in patients with rheumatoid arthritis (RA).MethodsAGI was assessed in vitro using human kidney cortical microsomes. Arterial function was measured clinically as the extent (augmentation index, AIX{\%}) and timing (reflected wave transit time, RWTT, msec) of arterial wave reflection using radial applanation pulse wave analysis (SphygmoCor PWA device) in 39 RA patients without overt CV disease aged 40-65. A higher AIX{\%} (and lower RWTT) indicates arterial dysfunction. Clinical assessment on a single occasion included a fasting blood sample, patient questionnaire and medical record review. Multivariable analysis was used to adjust for sex, mean blood pressure, arthritis duration, cumulative ESR-years and current DMARD therapy.ResultsThe inhibition constant (K-i) for celecoxib was lower than that of diclofenac (K-i 3.5 vs. 8.4 mu M). Chronic celecoxib use was associated with a higher AIX{\%} (34.8 vs. 32.3) and lower RWTT (130.1 vs. 132.7 msec) compared with diclofenac. Adjusted mean differences were AIX{\%} 4.7 (95{\%}CI 0.6 to 8.9; p=0.03) and RWTT -3.6 (95{\%}CI-10.0 to 2.7; p=0.26).ConclusionCelecoxib has a greater potency for AGI than diclofenac and its use is associated with a significantly higher AIX{\%}. Our findings support AGI as a plausible mechanism for the CV toxicity of NSAIDs.",
keywords = "rheumatoid arthritis, non-steroidal anti-inflammatory drugs, aldosterone, arterial dysfunction, pulse wave analysis, nonsteroidal antiinflammatory drugs, pulse-wave analysis, blood-pressure, cardiovascular mortality, augmentation index, stiffness, risk, metaanalysis, cyclo-oxygenase-2, cyclooxygenase",
author = "Crilly, {M. A.} and Mangoni, {A. A.} and Knights, {K. M.}",
year = "2013",
month = "9",
language = "English",
volume = "31",
pages = "691--698",
journal = "Clinical and Experimental Rheumatology",
issn = "0392-856X",
publisher = "CLINICAL & EXPER RHEUMATOLOGY",
number = "5",

}

TY - JOUR

T1 - Aldosterone glucuronidation inhibition as a potential mechanism for arterial dysfunction associated with chronic celecoxib and diclofenac use in patients with rheumatoid arthritis

AU - Crilly, M. A.

AU - Mangoni, A. A.

AU - Knights, K. M.

PY - 2013/9

Y1 - 2013/9

N2 - ObjectiveAdverse cardiovascular (CV) effects of non-steroidal anti-inflammatory drugs (NSAIDs) are largely independent of their cyclooxygenase (COX) enzyme selectivity, but could be a consequence of aldosterone 18 beta-glucuronidation inhibition (AGI), which varies between NSAIDS. This study assesses the chronic effects of celecoxib (selective COX-2 inhibitor) versus diclofenac (non-selective NSAID) therapy on arterial dysfunction in patients with rheumatoid arthritis (RA).MethodsAGI was assessed in vitro using human kidney cortical microsomes. Arterial function was measured clinically as the extent (augmentation index, AIX%) and timing (reflected wave transit time, RWTT, msec) of arterial wave reflection using radial applanation pulse wave analysis (SphygmoCor PWA device) in 39 RA patients without overt CV disease aged 40-65. A higher AIX% (and lower RWTT) indicates arterial dysfunction. Clinical assessment on a single occasion included a fasting blood sample, patient questionnaire and medical record review. Multivariable analysis was used to adjust for sex, mean blood pressure, arthritis duration, cumulative ESR-years and current DMARD therapy.ResultsThe inhibition constant (K-i) for celecoxib was lower than that of diclofenac (K-i 3.5 vs. 8.4 mu M). Chronic celecoxib use was associated with a higher AIX% (34.8 vs. 32.3) and lower RWTT (130.1 vs. 132.7 msec) compared with diclofenac. Adjusted mean differences were AIX% 4.7 (95%CI 0.6 to 8.9; p=0.03) and RWTT -3.6 (95%CI-10.0 to 2.7; p=0.26).ConclusionCelecoxib has a greater potency for AGI than diclofenac and its use is associated with a significantly higher AIX%. Our findings support AGI as a plausible mechanism for the CV toxicity of NSAIDs.

AB - ObjectiveAdverse cardiovascular (CV) effects of non-steroidal anti-inflammatory drugs (NSAIDs) are largely independent of their cyclooxygenase (COX) enzyme selectivity, but could be a consequence of aldosterone 18 beta-glucuronidation inhibition (AGI), which varies between NSAIDS. This study assesses the chronic effects of celecoxib (selective COX-2 inhibitor) versus diclofenac (non-selective NSAID) therapy on arterial dysfunction in patients with rheumatoid arthritis (RA).MethodsAGI was assessed in vitro using human kidney cortical microsomes. Arterial function was measured clinically as the extent (augmentation index, AIX%) and timing (reflected wave transit time, RWTT, msec) of arterial wave reflection using radial applanation pulse wave analysis (SphygmoCor PWA device) in 39 RA patients without overt CV disease aged 40-65. A higher AIX% (and lower RWTT) indicates arterial dysfunction. Clinical assessment on a single occasion included a fasting blood sample, patient questionnaire and medical record review. Multivariable analysis was used to adjust for sex, mean blood pressure, arthritis duration, cumulative ESR-years and current DMARD therapy.ResultsThe inhibition constant (K-i) for celecoxib was lower than that of diclofenac (K-i 3.5 vs. 8.4 mu M). Chronic celecoxib use was associated with a higher AIX% (34.8 vs. 32.3) and lower RWTT (130.1 vs. 132.7 msec) compared with diclofenac. Adjusted mean differences were AIX% 4.7 (95%CI 0.6 to 8.9; p=0.03) and RWTT -3.6 (95%CI-10.0 to 2.7; p=0.26).ConclusionCelecoxib has a greater potency for AGI than diclofenac and its use is associated with a significantly higher AIX%. Our findings support AGI as a plausible mechanism for the CV toxicity of NSAIDs.

KW - rheumatoid arthritis

KW - non-steroidal anti-inflammatory drugs

KW - aldosterone

KW - arterial dysfunction

KW - pulse wave analysis

KW - nonsteroidal antiinflammatory drugs

KW - pulse-wave analysis

KW - blood-pressure

KW - cardiovascular mortality

KW - augmentation index

KW - stiffness

KW - risk

KW - metaanalysis

KW - cyclo-oxygenase-2

KW - cyclooxygenase

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M3 - Article

VL - 31

SP - 691

EP - 698

JO - Clinical and Experimental Rheumatology

JF - Clinical and Experimental Rheumatology

SN - 0392-856X

IS - 5

ER -