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Treatment with drugs from multiple classes induces vascular injury with medial
necrosis, hemorrhage, endothelial damage, and inflammation. Previous research has
suggested early events might be occurring well in advance of the full lesions that
appear forty-eight to seventy-two hours after dosing with SCH 351591, a PDE IV
inhibitor. This study was performed to study early events in detail. Rats were dosed
with 20 mg/kg of drug by gavage and sacrificed at times between fifteen and 240
minutes after dosing. Tissues were collected for histopathological analysis and gene
expression studies. Serum was collected for biomarker analysis. The data from
biomarker analysis showed a three-part response with an early phase that was maximal
at fifteen to thirty minutes, a second phase from forty-five to 180 minutes, and the
third phase that was starting to rise at four hours. The first phase included
increases in lymphocytes, serum histamine, and serum nitrite. The second phase shows
continued elevation of serum nitrite. The third phase was marked by an increase in
serum GRO/CINC-1. At fifteen minutes, histopathology showed activation of mast cells,
but not degranulation. Increases in endothelial activation and perivascular
inflammatory cells were first apparent at thirty minutes and increased through 240
minutes.