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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 Open Access

Descriptions

Other title
Subject/Keyword
Anti-inflammatory
Glucosamine
Rat
Arachidonic acid
Adjuvant Arthritis
Renin-angiotensin system
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Aghazadeh Habashi, Ali
Supervisor and department
Jamali, Fakhreddin (Pharmaceutical Sciences)
Examining committee member and department
du Souich, Patrick (Pharmacology, University of Motreal)
Velazquez, Carlos (Pharmaceutical Sciences)
Vine, Donna (Agricultural, Food and Nutritional Sciences)
Sunwoo, Hoon (Pharmaceutical Sciences)
Brocks, Dion (Pharmaceutical Sciences)
Department
Faculty of Pharmacy and Pharmaceutical Sciences
Specialization
Pharmaceutical Sciences
Date accepted
2014-12-17T11:54:07Z
Graduation date
2015-06
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
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.
Language
English
DOI
doi:10.7939/R3KP7V04Z
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Aghazadeh-Habashi A, Jamali F. The glucosamine controversy; a pharmacokinetic issue. J Pharm Pharm Sci 2011;14(2):264-273Aghazadeh-Habashi A, Kohan MH, Asghar W, Jamali F. Glucosamine dose/concentration-effect correlation in the rat with adjuvant arthritis. J Pharm Sci 2014 Feb;103(2):760-767

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