EGFR-TKI, Erlotinib, Causes Hypomagnesemia, Oxidative Stress, and Cardiac Dysfunction
| Autor: | William B. Weglicki, I. Tong Mak, Christopher F. Spurney, Joanna J. Chmielinska, Jay H. Kramer |
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| Rok vydání: | 2015 |
| Předmět: |
Male
medicine.medical_specialty medicine.drug_class Morpholines Diastole Substance P Ventricular Function Left Article Hypomagnesemia Rats Sprague-Dawley Erlotinib Hydrochloride chemistry.chemical_compound Neurokinin-1 Receptor Antagonists Internal medicine medicine Animals Magnesium Protein Kinase Inhibitors Aprepitant Pharmacology Chemistry Nitrotyrosine Dilated cardiomyopathy Receptors Neurokinin-1 Receptor antagonist medicine.disease Rats ErbB Receptors Oxidative Stress Endocrinology Echocardiography Quinazolines Erlotinib Cardiology and Cardiovascular Medicine medicine.drug |
| Zdroj: | Journal of Cardiovascular Pharmacology. 65:54-61 |
| ISSN: | 0160-2446 |
| DOI: | 10.1097/fjc.0000000000000163 |
| Popis: | To determine whether the epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib may cause hypomagnesemia, inflammation, and cardiac stress, erlotinib was administered to rats (10 mg · kg(-1)· d(-1)) for 9 weeks. Plasma magnesium decreased progressively between 3 and 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 perivascular nitrotyrosine. The neurokinin-1 (NK-1) receptor antagonist, aprepitant (2 mg · kg(-1) · d(-1)), 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 the administration of the SP receptor blocker. |
| Databáze: | OpenAIRE |
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