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Design, synthesis, pharmacokinetics and pharmacodynamics of glucosamine related compounds for the treatment of arthritis
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- Author / Creator
- Gilzad Kohan, Mohammadhossein
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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. -
- Subjects / Keywords
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- A novel peptide prodrug of glucosamine with enhanced gut permeability
- The antiinflammatory action and pharmacokinetics of a novel di-peptide aminosugar
- Glucosamine and adjuvant arthritis: A pharmacokinetic and pharmacodynamic study
- Glucosamine: From nutraceutical to pharmaceutical
- Glucosamine prodrugs
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- Graduation date
- Fall 2013
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- Type of Item
- Thesis
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- Degree
- Doctor of Philosophy
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- 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.