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

Sherif Mahmoud
2010
Dedication To my lovely wife Sally, for being my soul To my lovely Mom and Dad, for setting the stage for my life To My wonderful Mom and Dad-in law, for their continuous support To My precious Basant and Omar, for being the pearls of my life To Dr Jamali, for his guidance to my scientific maturity 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
more » ... 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 (Ca v 1.2) 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 Ca v 1.2 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.
doi:10.7939/r3zk8f fatcat:upkhoponkjchnl5osupi5kupnu