Relationships between thromboxane production, platelet aggregability, and serum concentrations of ibuprofen or flurbiprofen.

Arachidonate-induced ex vivo platelet aggregations were performed before and after subjects received various doses of either ibuprofen or flurbiprofen. Both ibuprofen and flurbiprofen reduced the initial rate of thromboxane B2 (TxB2) production, but about 10% of control TxB2 production was refractory to either drug. Aggregation was observed after TxB2 concentrations exceeded a threshold of about 40 ng/ml. Once the threshold was achieved, aggregation and TxB2 production occurred independently of either drug. Ibuprofen and flurbiprofen concentrations of about 3 and 0.2 micrograms/ml, respectively, inhibited aggregation during the 5-minute testing period. A pharmacodynamic model was developed that predicts TxB2 production, aggregation lag times, and percent aggregation as a function of the time course of drug concentrations in serum.

Aspirin-induced damage in the dog Heidenhain pouch and cytoprotection with 16,16-dimethyl PGE2.

The gastric mucosa of animals and man can be damaged by noxious agents and protected by prostaglandins. We developed a Heidenhain pouch dog model which allows the study of multiple doses of the protective or noxious agent. Mucosal damage in the pouch caused by instillation of 160 mM aspirin suspended in 150 mM HCl for two 15-min periods was determined by measuring hemoglobin concentration in isotonic mannitol washes. Hemoglobin levels 24 h after the administration of the acid-aspirin suspension were significantly higher than basal levels. Pretreatment with oral doses of 0.3-3 micrograms/kg 16,16-dimethyl PGE2 at 24 and 18 h and 30 min before the acid-aspirin suspension decreased hemoglobin concentrations in the washes (p less than 0.001).