{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T01:38:44Z","timestamp":1780969124986,"version":"3.54.1"},"reference-count":27,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2012,8,31]],"date-time":"2012-08-31T00:00:00Z","timestamp":1346371200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Applied Toxicology"],"published-print":{"date-parts":[[2012,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>PF\u201004254644 is a selective kinase inhibitor of mesenchymal epithelial transition factor\/hepatocyte growth factor receptor with known off\u2010target inhibitory activity against the phosphodiesterase (PDE) family. Rats given repeated oral doses of PF\u201004254644 developed a mild to moderate myocardial degeneration accompanied by sustained increase in heart rate and contractility. Investigative studies were conducted to delineate the mechanisms of toxicity. Microarray analysis of Sprague\u2013Dawley rat hearts in a 6\u2009day repeat dose study with PF\u201004254644 or milrinone, a selective PDE3 inhibitor, revealed similar perturbation of the cyclic adenosine monophosphate (c\u2010AMP) pathway. PDE inhibition and activation of c\u2010AMP were further substantiated using PDE3B immunofluorescence staining and through a c\u2010AMP response element reporter gene assay. The intracellular calcium and oxidative stress signaling pathways were more perturbed by treatment with PF\u201004254644 than milrinone. The rat cardiomyocytes calcium assay found a dose\u2010dependent increase in intracellular calcium with PF\u201004254644 treatment. These data suggest that cardiotoxicity of PF\u201004254644 was probably due to activation of c\u2010AMP signaling, and possibly subsequent disruption of intracellular calcium and oxidative stress signaling pathways. The greater response with PF\u201004254644 as compared with milrinone in gene expression and micro\u2010 and ultrastructural changes is probably due to the broader panel of PDEs inhibition. Copyright \u00a9 2012 John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/jat.2801","type":"journal-article","created":{"date-parts":[[2012,8,31]],"date-time":"2012-08-31T06:35:09Z","timestamp":1346394909000},"page":"1008-1020","source":"Crossref","is-referenced-by-count":8,"title":["A tyrosine kinase inhibitor\u2010induced myocardial degeneration in rats through off\u2010target phosphodiesterase inhibition"],"prefix":"10.1002","volume":"32","author":[{"given":"Wenyue","family":"Hu","sequence":"first","affiliation":[{"name":"Pfizer Inc Drug Safety Research and Development, La Jolla Laboratories  10646 Science Center Drive San Diego CA 92121 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brad","family":"Hirakawa","sequence":"additional","affiliation":[{"name":"Pfizer Inc Drug Safety Research and Development, La Jolla Laboratories  10646 Science Center Drive San Diego CA 92121 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart","family":"Jessen","sequence":"additional","affiliation":[{"name":"Pfizer Inc Drug Safety Research and Development, La Jolla Laboratories  10646 Science Center Drive San Diego CA 92121 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Lee","sequence":"additional","affiliation":[{"name":"Pfizer Inc Drug Safety Research and Development, La Jolla Laboratories  10646 Science Center Drive San Diego CA 92121 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shirley","family":"Aguirre","sequence":"additional","affiliation":[{"name":"Pfizer Inc Drug Safety Research and Development, La Jolla Laboratories  10646 Science Center Drive San Diego CA 92121 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,8,31]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1177\/0192623310364027"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.58.3.5"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.206920"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pcad.2010.06.006"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(07)61865-0"},{"key":"e_1_2_6_7_1","first-page":"864","article-title":"Biochemical mechanisms for the inotropic effect of the cardiotonic drug milrinone","volume":"8","author":"Earl CQ","year":"1986","journal-title":"J. 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