Biomarkers in peripheral blood associated with vascular injury in Sprague-Dawley rats treated with the phosphodiesterase IV inhibitors SCH 351591 or SCH 534385.
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, alpha1-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.
Weaver
James L
JL
Division of Applied Pharmacology Research, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland 20993-0002, USA. james.weaver@fda.hhs.gov
Snyder
Ronald
R
Knapton
Alan
A
Herman
Eugene H
EH
Honchel
Ronald
R
Miller
Terry
T
Espandiari
Parvaneh
P
Smith
Roger
R
Gu
Yi-Zhong
YZ
Goodsaid
Federico M
FM
Rosenblum
Irwin Y
IY
Sistare
Frank D
FD
Zhang
Jun
J
Hanig
Joseph
J
D000818:Animals; D015415:Biomarkers / Q000097:blood*; D001808:Blood Vessels / Q000187:drug effects*; D019963:Clinical Chemistry Tests; D003497:Cyclic N-Oxides / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D007150:Immunohistochemistry; D007958:Leukocyte Count; D008638:Mesenteric Arteries / Q000473:pathology; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000633:toxicity*; D011804:Quinolines / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014652:Vascular Diseases / Q000097:blood / Q000139:chemically induced* / Q000473:pathology
D015415:Biomarkers; D003497:Cyclic N-Oxides; D009566:Nitrates; D009573:Nitrites; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D011804:Quinolines; C459379:SCH 351591