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Dose – Dependency of The Cardiovascular Risks of Non-Steroidal Anti-Inflammatory Drugs

  • Author / Creator
    Ahmed, Surur Ali
  • Abstract Rheumatoid arthritis (RA) is a chronic, progressive, and systemic inflammatory condition leading to joint destruction, substantial pain, and functional disability. Patients with RA have a higher morbidity and mortality rate because of cardiovascular (CV) complications than the general population. Non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat pain and inflammation associated with arthritis. However, NSAIDs are also known to elevate CV risks, but the mechanism by which this occurs is unknown. More attention has been paid recently to CV and the renal safety profile of NSAIDs, starting with the withdrawal of rofecoxib from the market because of increasing risk of thromboembolic events such as heart attack and stroke. However, not all NSAIDs are considered to cause major CV effects. The intrinsic pharmacological and pharmacokinetic properties of NSIADs could be involved in causing CV risks. Some data suggest of lack of CV complications at lower therapeutic doses of some NSAIDs. Recently, ample recent preclinical data suggest that modulating of eicosanoids, the cytochrome P450 (CYP) metabolites of arachidonic acid (ArA), may be a potential clinical therapeutic strategy and achievable biomarker to manage different pathological disorders, in particular CV diseases. Taken together, we hypothesize that the CV risk NSAIDs is dose-dependent so that for diclofenac, an NSAIDs with known severe CV complications, lower therapeutic doses are void of the above side effect. We i) used adjuvant arthritis (AA) as an experimental model of arthritis; ii) dosed rats with a range of diclofenac doses to control AA; iii) identified the effective dosage range; and iv) euthanize the animals and assessed the effect of the treatments on CYP-ArA pathway, and determined drug concentrations in selected tissues. Our results show i) a dose-dependent effect for the diclofenac dosage range used; ii) that extent of accumulation of diclofenac in the heart was dose-dependent; iii) that low therapeutic doses did not alter the CYP-mediated ArA metabolism, while high doses of diclofenac in inflamed rats suggest an increase in the 20-HETE/EETs (cardio-toxic/cardioprotective) metabolites concentration in the plasma and heart of AA rats. This was while. In conclusion, within the therapeutic range, only the examined high doses of diclofenac caused imbalances in ArA metabolic patterns toward cardiotoxicity. This is suggestive of dose- and exposure-dependency of NSAID cardiotoxicity, and low therapeutic doses may be void of CV side effects. Human studies are needed to examine the safety of low but effective doses of NSAIDs.

  • Subjects / Keywords
  • Graduation date
    2017-11:Fall 2017
  • Type of Item
    Thesis
  • Degree
    Master of Science
  • DOI
    https://doi.org/10.7939/R3445HS2V
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Master's
  • Department
    • Faculty of Pharmacy and Pharmaceutical Sciences
  • Specialization
    • Pharmaceutical Sciences
  • Supervisor / co-supervisor and their department(s)
    • Jamali, Fakhreddin (Pharmaceutical Sciences)
  • Examining committee members and their departments
    • Mahmoud, Sherif (Pharmacy Practice)
    • Loebenberg, Raimar (Pharmaceutical Sciences)