Disturbance of macrophage and monocyte function in the dog by a thromboxane receptor antagonist: ICI 185,282.
ICI 185,282 is a specific thromboxane receptor antagonist developed by ZENECA Pharmaceuticals for potential use in the treatment of inflammatory disease. During safety evaluation in dogs, multifocal granulomatous infiltrates occurred in multiple organs at high dose levels. These consisted predominantly of enlarged histiocytic cells. We reported a 28-day investigative study in which Millipore filters overlaid with carbon were implanted subcutaneously. Histological assessment of the developing foreign body granulomatous tissue response and evaluation of in vitro migration of peripheral blood monocytes were performed. The development of epithelioid macrophages with altered behavior, modification of fibroplasia, and increased monocyte infiltration at the implant site resulted from administration of ICI 185,282. This was accompanied by enhanced migration of isolated peripheral blood monocytes in vitro. We believe that the granulomatous infiltrates that occurred during toxicological assessment in dogs may be a result of a drug-induced disturbance in macrophage response to concurrent subclinical inflammations or alteration in the normal disposition of tissue macrophages, i.e., they were a result of an atypical response to a concurrent stimulus for macrophage activity.
Westwood
F R
FR
Safety of Medicines Department, ZENECA Pharmaceuticals, Macclesfield, Cheshire, United Kingdom.
Duffy
P A
PA
Malpass
D A
DA
Jones
H B
HB
Topham
J C
JC
D000284:Administration, Oral; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D004146:Dioxanes / Q000008:administration & dosage / Q000633:toxicity*; D004285:Dogs; D004343:Drug Implants / Q000633:toxicity; D005260:Female; D006099:Granuloma / Q000209:etiology; D008099:Liver / Q000473:pathology; D008168:Lung / Q000473:pathology; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects*; D008297:Male; D009000:Monocytes / Q000187:drug effects*; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*
D004146:Dioxanes; D004343:Drug Implants; D017482:Receptors, Thromboxane; C059061:ICI 185282