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EGFR-TKI, Erlotinib, Causes Hypomagnesemia, Oxidative Stress and Cardiac Dysfunction: Attenuation by NK-1 Receptor Blockade.
MedLine Citation:
PMID:  25343568     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
To determine whether the EGFR tyrosine kinase inhibitor, erlotinib may cause hypomagnesemia, inflammation and cardiac stress, erlotinib was administered to rats (10 mg/kg/day) for 9 weeks. Plasma magnesium decreased progressively between 3-9 weeks (-9 to -26%). Modest increases in plasma substance P (SP) occurred at 3 (+27%) and 9 (+25%) weeks. Neutrophil superoxide-generating activity increased 3-fold, and plasma 8-isoprostane rose 210%, along with noticeable appearance of cardiac peri-vascular nitrotyrosine. The neurokinin-1 (NK-1) receptor antagonist, aprepitant (2 mg/kg/day), attenuated erlotinib-induced hypomagnesemia up to 42%; reduced circulating SP, suppressed neutrophil superoxide activity and 8-isoprostane elevations; cardiac nitrotyrosine was diminished. Echocardiography revealed mild to moderately decreased left ventricular ejection fraction (-11%) and % fractional shortening (-17%) by 7 weeks of erlotinib treatment, and significant reduction (-17.5%) in mitral valve E/A ratio at week 9, indicative of systolic and early diastolic dysfunction. Mild thinning of the left ventricular posterior wall suggested early dilated cardiomyopathy. Aprepitant completely prevented the erlotinib-induced systolic and diastolic dysfunction, and partially attenuated the anatomical changes. Thus, chronic erlotinib treatment does induce moderate hypomagnesemia, triggering SP-mediated oxidative/inflammation stress, and mild to moderate cardiac dysfunction, which can largely be corrected by administration of the SP receptor blocker.
Authors:
I Tong Mak; Jay H Kramer; Joanna J Chmielinska; Christopher F Spurney; William B Weglicki
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-10-23
Journal Detail:
Title:  Journal of cardiovascular pharmacology     Volume:  -     ISSN:  1533-4023     ISO Abbreviation:  J. Cardiovasc. Pharmacol.     Publication Date:  2014 Oct 
Date Detail:
Created Date:  2014-10-24     Completed Date:  -     Revised Date:  2014-10-25    
Medline Journal Info:
Nlm Unique ID:  7902492     Medline TA:  J Cardiovasc Pharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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