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Drug-disease interaction: effect of inflammation on the pharmacological response to calcium channel blockers Open Access

Descriptions

Other title
Subject/Keyword
Inflammation
Calcium channel blockers
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Mahmoud, Sherif
Supervisor and department
Jamali, Fakhreddin (Faculty of Pharmacy and Pharmaceutical Sciences)
Examining committee member and department
Seubert, John (Faculty of Pharmacy and Pharmaceutical Sciences)
Jamali, Fakhreddin (Faculty of Pharmacy and Pharmaceutical Sciences)
Pinsk, Maury (Faculty of Medicine, Pediatric Nephrology)
Sitar, Daniel S. (Faculty of Medicine, Pharmacology and Therapeutics, University of Manitoba)
El-Kadi, Ayman (Faculty of Pharmacy and Pharmaceutical Sciences)
Brocks, Dion (Faculty of Pharmacy and Pharmaceutical Sciences)
Department
Faculty of pharmacy and pharmaceutical sciences
Specialization

Date accepted
2010-09-30T16:10:23Z
Graduation date
2010-11
Degree
Doctor of philosophy
Degree level
Doctoral
Abstract
The present research is focused on the topic of inflammation-drug interaction. Inflammation complicates many human diseases and conditions ranging from obesity to cancer. Therefore, the study of the effect of inflammation on drug pharmacokinetics and pharmacodynamics is pivotal. First, we tested the hypothesis that controlling inflammation using valsartan can restore the previously reported altered verapamil pharmacokinetics and pharmacodynamics. Such an effect is expected due to the anti-inflammatory properties of angiotensin II inhibition. Inflammation resulted in L-type calcium channel target protein (Cav1.2) downregulation and reduced verapamil potency in pre-adjuvant arthritis rat model. Valsartan treatment reversed the observed downregulation of L-type calcium channels thereby enhancing verapamil potency. This beneficial interaction, once proven in humans, may be of value in cardiac patients with superimposing inflammatory diseases. Second, we investigated whether the response to verapamil is reduced in experimentally induced acute myocardial injury (AMI) in rats. AMI caused a 75% reduction in verapamil potency and Cav1.2 target protein downregulation. If extrapolated to humans, our observations may suggest that L-type calcium channel downregulation can contribute, at least in part, to the poor outcome in myocardial infarction patients treated with calcium channel blockers (CCBs). Third, we studied the effect of obesity on the pharmacological response of CCBs in children with renal disease. Our data indicated that obese children are less responsive to CCBs than non-obese ones. Therefore, obesity should be considered when initiating antihypertensive drug therapy in children. Last, we were interested in finding out if the expression of other target genes is also altered by inflammation. We used real time polymerase chain reaction, after determination of the best housekeeping gene to be used as an internal control. Inflammation resulted in significant alterations of several molecular targets and transporters affecting the pharmacokinetics and pharmacodynamics of drugs. These findings may provide an insight into the effect of inflammation on drug targets and modulators of disease pathogenesis. In conclusion, inflammation is a missed ring in the chain of therapy. The research presented in this thesis will add to the inflammation-drug interaction field important findings that will help understanding the role of inflammation in pharmacotherapy outcomes.
Language
English
DOI
doi:10.7939/R3ZK8F
Rights
License granted by Sherif Mahmoud (smahmoud@ualberta.ca) on 2010-09-29T21:52:00Z (GMT): 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 the above terms. The author reserves all other publication and other rights in association with the copyright in the thesis, and except as herein 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.
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