Experimental pancytopenia of the peripheral blood with granulocytopoietic bone marrow hyperplasia in the beagle-dog.
During subacute and chronic toxicity studies on beagle dogs with the platelet aggregation inhibitor UH-A 46 XX, a suboxicam derivative, a pancytopenia of the peripheral blood with granulocytopoietic bone marrow hyperplasia was induced. Our observations are based on the results of a 13 week routine experiment (control group and dosage groups 5-, 50- and 700 mg/kg per day UH-A 46 XX) and on a special open-ended reversibility study (control group and dosage groups 50- and 700 mg/kg). The reversibility study included closely monitored hematological controls, bone-marrow cytology from sternal punctures and plastic section histology of iliac crest biopsies. During this study, plasma levels of the substance were estimated. The reproducible syndrome described was similar in the dogs in both studies. As early as the 8th week, but mostly between the 9th and 12th experimental weeks, one third of the animals treated orally with 700 mg/kg b.wt. UH-A 46 XX per day developed an acute fever (10 out of 30 animals). Four died several days later. Dogs treated with 5 or 50 mg/kg UH-A 46 XX remained unaffected. In the diseased dogs in both studies, proven pancytopenia was associated with the occurrence of numerous hematopoietic, especially granulocytopoietic precursors. The hyperplastic bone marrow showed a massive increase in granulocytopoiesis with considerable maturation arrest. These processes were accompanied by suppression or reduction of erythropoiesis. In addition, histological findings in the animals that died showed extramedullary hematopoiesis in different organs. During the second study, the reversibility was investigated in sick animals. If substance administration was terminated when the illness had reached its peak, normalization occurred quickly within 2 to 3 weeks. The animals remained healthy until the end of the long term follow-up which varied from 9 to 10 months. The pathogenesis of pancytopenia caused by UH-A 46 XX seems to be a chemically induced hyperdestruction of the peripheral blood cells. This appraisal is supported by the clear degenerative alterations in the granulocytic cells of the peripheral blood. An additional inhibitory effect of UH-A 46 XX on cellular maturation processes of hematopoiesis can be assumed.
Schneider
P
P
Department of Experimental Pathology and Toxicology, Dr Karl Thomae GmbH, Biberach/Riss, FRG.
Bauer
M
M
Busch
U
U
Meister
H
H
D000284:Administration, Oral; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology*; D002452:Cell Count; D004285:Dogs; D004909:Erythrocyte Indices; D005260:Female; D006098:Granulocytes; D006410:Hematopoiesis / Q000187:drug effects*; D006965:Hyperplasia / Q000139:chemically induced; D008297:Male; D008854:Microscopy, Electron; D010198:Pancytopenia / Q000097:blood / Q000139:chemically induced* / Q000473:pathology; D010894:Piroxicam / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D013997:Time Factors
D010894:Piroxicam; C065450:UH-A 46 XX