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 ofinflammat ory disease. During safety evaluation in dogs, multifocal granulomatou s infiltrates occurred in multiple organs at high dose levels. These c onsisted predominantly of enlarged histiocytic cells. We report a 28-d ay investigative study in which Millipore filters overlaid with carbon were implanted subcutaneously. Histological assessment of the develop ing foreign body granulomatous tissue response and evaluation of in vi tro migration of peripheral blood monocytes were performed. The develo pment of epithelioid macrophages with altered behavior, modification o f 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 toxic ological assessment in dogs may be a result of a drug-induced disturba nce 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 ma crophage activity.