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Permanent link (DOI): https://doi.org/10.7939/R36970484

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Design, synthesis, pharmacokinetics and pharmacodynamics of glucosamine related compounds for the treatment of arthritis Open Access

Descriptions

Other title
Subject/Keyword
Glucosamine prodrugs
The antiinflammatory action and pharmacokinetics of a novel di-peptide aminosugar
Glucosamine: From nutraceutical to pharmaceutical
Glucosamine and adjuvant arthritis: A pharmacokinetic and pharmacodynamic study
A novel peptide prodrug of glucosamine with enhanced gut permeability
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Gilzad Kohan, Mohammadhossein
Supervisor and department
Jamali, Fakhreddin (Faculty of Pharmacy and Pharmaceutical Sciences, university of Alberta)
Kaur, Kamaljit (Faculty of Pharmacy and Pharmaceutical Sciences, university of Alberta)
Examining committee member and department
Brocks, Dion (Faculty of Pharmacy and Pharmaceutical Sciences, university of Alberta)
Löbenberg, Raimar (Faculty of Pharmacy and Pharmaceutical Sciences, university of Alberta)
Anderson, Hope (Faculty of Pharmacy, University of Manitoba)
Baker, Glen B ( Department of Psychiatry; Faculty of Medicine & Dentistry, University of Alberta)
Kaur, Kamaljit (Faculty of Pharmacy and Pharmaceutical Sciences, university of Alberta)
Jamali, Fakhreddin (Faculty of Pharmacy and Pharmaceutical Sciences, university of Alberta)
Department
Faculty of Pharmacy and Pharmaceutical Sciences
Specialization
Pharmaceutical Sciences
Date accepted
2013-07-23T14:45:02Z
Graduation date
2013-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
There are several animal studies reporting strong disease-modifying effects and anti-inflammatory properties of glucosamine (GlcN). The anti-inflammatory properties of GlcN have suggested its use to treat inflammatory diseases such as adjuvant arthritis (AA). In this study, we showed that administration of GlcN at a dose of 300 mg/kg/day prevented arthritis and improved the signs and symptoms after their emergence. In addition, GlcN restored the down-regulating effect of AA on cardiac proteins and response to verapamil. However, clinical trials in humans are flawed; while some studies suggested effectiveness, others were inconclusive, with their results ranging from strongly effective to negligible or no benefit to the patients. The oral bioavailability (BA) of GlcN is limited and this is, at least in part, behind the controversy in the effectiveness of GlcN. Hence, the development of a GlcN pro-drug with improved BA should render beneficial effect in controlling inflammatory conditions. Fifteen peptide GlcN derivatives were synthesized consisting of eight esters and seven amides. Their stability was assessed at elevated temperature, high and low pH, and exposure to intestinal and liver homogenates. In addition, their permeability through rat jejunum sacks was evaluated. All of the ester and amide conjugates exhibited favorable thermal and chemical stability. Only a few di-peptide esters exhibited reasonable stability in the intestine and rapid degradation in the liver homogenates. Furthermore, only Gly-Val-COO-GlcN (GVG) exhibited a significant increase in gut permeability relative to GlcN. The mechanism for membrane permeation is believed to occur via the peptide transporter 1 (PepT1), because a competition assay with the PepT1 substrate, Gly-Sar, blocked GVG gut permeability. Furthermore GVG was examined for its BA and efficacy to prevent AA. The stability of the GVG was also tested after incubation with rat feces. GVG showed significantly higher plasma concentrations and urinary excretion than GlcN (≈3-fold increase). GVG showed a favorable stability in rat feces. Adjuvant arthritis was completely prevented with doses greater than 20 mg/kg/day, with GVG being 3-fold more potent than GlcN. In conclusion, GVG appears to be a potent anti-inflammatory compound due to its favorable properties to deliver GlcN into the systemic circulation.
Language
English
DOI
doi:10.7939/R36970484
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
Glucosamine and adjuvant arthritis: A pharmacokinetic and pharmacodynamic study. Mohammad H. Gilzad-Kohan, Fakhreddin Jamali, European Journal of Pharmaceutical Sciences 47 (2012) 387–393.The Antiinflammatory Action and Pharmacokinetics of a Novel Di-peptide Aminosugar. Mohammad H. Gilzad-Kohan, Kamaljit Kaur and Fakhreddin Jamali, J Pharm Pharm Sci,16(2) 279 - 288, 2013

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