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Glucosamine Anti-Inflammatory Dose-Effect Correlation and Its Influence on the Renin-Angiotensin System Components and Arachidonic Acid Metabolites under Inflammatory Condition in the Rat with Adjuvant Arthritis

  • Author / Creator
    Aghazadeh Habashi, Ali
  • Crystalline glucosamine (GlcN) sulfate salt formulation is approved as a prescription drug with anti-inflammatory effects for the management of osteoarthritis (OA) in the European Union, while it is considered as a nutraceutical in North America. The effectiveness of GlcN for ameliorating the signs and symptoms of OA in humans is still the subject of scientific debate. In animal studies using high doses, its effectiveness is undisputable; however results of clinical trials in humans are controversial. One of the objectives of this thesis was to address the possible causes of controversy around GlcN effectiveness in humans, and to establish a minimum effective dose (MED) needed to produce minimum anti-inflammatory effective concentration in the rat adjuvant arthritis animal model. Many explanations have been offered as the root of the controversy including superiority of a crystalline sulfate salt over the hydrochloride form, industry bias, insensitive assessment metrics, and poor methodology. Herein, we rule out a difference in bioequivalence between GlcN salts and suggest additional factors; i.e., inconsistency in the GlcN content of some products used in trials, under-dosing of patients, as well as variable pharmacokinetic indices as possible reasons for the lack of GlcN efficacy observed in some studies. Clinical trials using high doses of pharmaceutical grade GlcN, or formulations with greater bioavailability should yield positive results. Our results indicate that the MED is between 40 to 80 mg/kg/day that generates a maximum plasma concentration in the range of 1.37 ± 0.24 to 5.31± 6.84 mg/L, close to the rang of concentration reported for pharmaceutical grades of GlcN in humans. GlcN efficacy is dose and concentration dependent and if the data could be extrapolated to humans, using a higher than the commonly tested 1500 mg/kg /day dosage regimen may provide more clear treatment outcomes. Inflammation influences the body as whole and imbalances the homeostasis of different regulatory systems in particular. Renin-angiotensin system (RAS) and arachidonic acid (ArA) pathway are two main regulators of cardiovascular (CV) systems which could be affected by inflammation. Other objectives of this thesis were to investigate if experimentally induced adjuvant arthritis (AA), as an animal model for systemic inflammation, alters different components of the RAS such as angiotensin converting enzymes (ACE) expression, angiotensin (Ang) peptides systemic and local concentration, and their associated receptors expression level. We also investigated the effect of AA on ArA metabolites concentration in the plasma, heart and kidney tissues. We correlated the RAS components and ArA metabolites concentration in order to identify reliable biomarkers for prediction of CV complications in vulnerable individuals suffering from inflammatory conditions such as rheumatoid arthritis (RA). GlcN with anti-inflammatory effects is a good candidate for modulating the detrimental effect of inflammation on the RAS and ArA pathways. We studied the impact of GlcN on these two systems. GlcN was able to reestablish the disturbed balance of the RAS and ArA pathway by reinstating the ratio of cardioprotective (vasodilator, anti-proliferative and anti-hypertrophic) over cardiotoxic (vasoconstrictive, proliferative and pro-hypertrophic) components of these systems. GlcN by presenting modulatory effects on the RAS and ArA pathways could be an alternative over NSAIDs which their long term use imposes CV side effects in RA patients.

  • Subjects / Keywords
  • Graduation date
    2015-06
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3KP7V04Z
  • 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
    Doctoral
  • 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
    • du Souich, Patrick (Pharmacology, University of Motreal)
    • Velazquez, Carlos (Pharmaceutical Sciences)
    • Vine, Donna (Agricultural, Food and Nutritional Sciences)
    • Brocks, Dion (Pharmaceutical Sciences)
    • Sunwoo, Hoon (Pharmaceutical Sciences)