D-4396

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.

This report describes the findings of preclinical testing of SCH 351591, a selective phosphodiesterase 4 inhibitor, in CD-1 mice over a wide range of doses, in which the heart and reproductive organs of both sexes demonstrated toxic effects. Repeat-dose toxicity studies assessed 5, 15, 50, 100, 200, 400, and 800 mg/kg/day, orally by gavage, for one or three months. Findings included higher testes and ovary weights and lower uterus weights (≥200 mg/kg), small ovaries/uterus (≥400 mg/kg), and histopathologic changes of large corpora lutea and ovarian atrophy at 200 and 800 mg/kg, respectively. In addition, chronic myocardial inflammation of the heart base occurred at 100 mg/kg. Vaginal staging of the estrous cycle revealed persistent diestrus. There was no histopathologic correlate or morphometric change to explain higher testes weights. A pilot fertility and early embryonic developmental toxicity study assessing doses of 100, 200, 400, and 800 mg/kg/day produced complementary results. Females had prolonged or abnormal estrous cycles, fewer successful pregnancies, increased ovarian corpora lutea, and decreased size of live litters owing to fetal resorptions. Male fertility was not affected. However, males had a 25% increase in testes weights at all doses. The pharmacology of specific PDE4 isoenzymes may explain both the reproductive and cardiac findings.