Leukocyte and bone marrow effects of a thiomorpholine quinazosin antihypertensive agent

PD-88823, a thiomorpholine analog of prazosin, induced a consistent dose-related suppression of granulopoiesis with subsequent neutropenia and leukopenia in rats and dogs. Rats treated at 600 mg kg-1 day-1 had neutrophil counts reduced by 44% in males and 30% in females after 13 weeks. A 4-week observation period after drug treatment resulted in a rebound in neutrophil counts to 123 and 215% of control values in males and females, respectively. White blood cell count reductions were less evident in dogs, probably because of the lower doses. In both species, the extent of bone marrow suppression was related to duration of treatment. No other hematologic changes were manifest in either species. The mechanism for bone marrow depression and subsequent granulocytopenia was not established. The lack of reported bone marrow effects by quinazosin analogs suggests that the thiomorpholine group of PD-88823 is involved in toxicity. This correlation may be important to safety considerations for future drug design.