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Toxicologic Pathology
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Articles

Biomarkers in Peripheral Blood Associated with Vascular Injury in Sprague-Dawley Rats Treated with the Phosphodiesterase IV Inhibitors SCH 351591 or SCH 534385

James L. Weaver, PhD1, Ronald Snyder, PhD2, Alan Knapton, BS1, Eugene H. Herman, PhD1, Ronald Honchel, PhD1, Terry Miller, PhD1, Parvaneh Espandiari, PhD1, Roger Smith, MS2, Yi-Zhong Gu, PhD2, Federico M. Goodsaid, PhD3, Irwin Y. Rosenblum, PhD4, Frank D. Sistare, PhD5, Jun Zhang, MD1 and Joseph Hanig, PhD1

1 Division of Applied Pharmacology Research, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA
2 Schering-Plough Research Institute, Summit, New Jersey, USA
3 Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA
4 Kyowa Pharmaceutical Inc., Princeton, New Jersey, USA
5 Merck Research Laboratories, West Point, Pennsylvania, USA

Correspondence: James L. Weaver, Division of Applied Pharmacology Research, Life Science Building 64, HFD-910, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002, USA; E-mail:james.weaver{at}fda.hhs.gov.

Drug-associated vascular injury can be caused by phosphodiesterase (PDE) IV inhibitors and drugs from several other classes. The pathogenesis is poorly understood, but it appears to include vascular and innate immunological components. This research was undertaken to identify changes in peripheral blood associated with vascular injury caused by PDE IV inhibitors. We evaluated twelve proteins, serum nitrite, and leukocyte populations in peripheral blood of rats treated with experimental PDE IV inhibitors. We found that these compounds produced histological microvascular injury in a dose- and time-dependent manner. Measurement of these serum proteins showed changes in eight of the twelve examined. Changes were seen in the levels of: tissue inhibitor of metalloproteinase-1, {alpha}1-acid glycoprotein, GRO/CINC-1, vascular endothelial growth factor, C-reactive protein, haptoglobin, thrombomodulin, and interleukin-6. No changes were seen in levels of tumor necrosis factor-{alpha}, hepatocyte growth factor, nerve growth factor, and granulocyte-monocyte colony stimulating factor. Serum levels of nitrite were also increased. Circulating granulocyte numbers were increased, and lymphocyte numbers were decreased. The changes in these parameters showed both a dose- and time-dependent association with histopathologic changes. These biomarkers could provide an additional tool for the nonclinical and clinical evaluation of investigational compounds.

Key Words: microvascular injury • biomarkers • phosphodiesterase inhibitors

Abbreviations: {alpha}1-AGP, {alpha}1-acid glycoprotein • CRP, C-reactive protein • DIVI, drug-induced vascular injury • eNOS, endothelial nitric oxide synthase • GM-CSF, granulocyte monocyte colony stimulating factor • HGF, hepatocyte growth factor • IL-6, interleukin-6 • iNOS, inducible nitric oxide synthase • MCP-1, monocytes chemotactic protein-1 • MIP-1, macrophage inhibitory protein-1 • TIMP-1, tissue inhibitor of metalloproteinase-1 • TM, thrombomodulin • TNF-{alpha}, tumor necrosis factor-{alpha} • VEGF, vascular endothelial growth factor

This version was published on October 1, 2008

Toxicologic Pathology, Vol. 36, No. 6, 840-849 (2008)
DOI: 10.1177/0192623308322310
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Home page
 Toxicol PatholHome page
J. Zhang, R. D. Snyder, E. H. Herman, A. Knapton, R. Honchel, T. Miller, P. Espandiari, F. M. Goodsaid, I. Y. Rosenblum, J. P. Hanig, et al.
Histopathology of Vascular Injury in Sprague-Dawley Rats Treated with Phosphodiesterase IV Inhibitor SCH 351591 or SCH 534385
Toxicol Pathol, October 1, 2008; 36(6): 827 - 839.
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