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Biomarkers in peripheral blood associated with vascular injury in Sprague-Dawley rats treated with the phosphodiesterase IV inhibitors SCH 351591 or SCH 534385.
- Source :
-
Toxicologic pathology [Toxicol Pathol] 2008 Oct; Vol. 36 (6), pp. 840-9. Date of Electronic Publication: 2008 Sep 05. - Publication Year :
- 2008
-
Abstract
- 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.
- Subjects :
- Animals
Clinical Chemistry Tests
Dose-Response Relationship, Drug
Immunohistochemistry
Leukocyte Count
Mesenteric Arteries pathology
Nitrates blood
Nitrites blood
Rats
Rats, Sprague-Dawley
Vascular Diseases blood
Vascular Diseases pathology
Biomarkers blood
Blood Vessels drug effects
Cyclic N-Oxides toxicity
Phosphodiesterase 4 Inhibitors
Phosphodiesterase Inhibitors toxicity
Quinolines toxicity
Vascular Diseases chemically induced
Subjects
Details
- Language :
- English
- ISSN :
- 1533-1601
- Volume :
- 36
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Toxicologic pathology
- Publication Type :
- Academic Journal
- Accession number :
- 18776166
- Full Text :
- https://doi.org/10.1177/0192623308322310