Beneficial effects of UK 37248, a thromboxane synthetase inhibitor, in experimental endotoxic shock in the rat.

Abstract 1 The effects of pretreatment with the thromboxane synthetase inhibitor UK 37248 (dazoxiben) administered 30 min before intravenous endotoxin (S. enteriditis) in the rat was investigated. 2 Plasma prostaglandins and thromboxanes were determined via radioimmunoassay. Endotoxaemia was associated with significant elevations above control values (<200 pg/ml) in plasma thromboxane B2 (TXB2), prostaglandin E (PGE) and 6-keto-prostaglandin F1α (6-keto-PGF1α). Within 30 min after endotoxin administration plasma immunoreactive (i) iTXB2 was 875±90pg/ml (n=9), iPGE was 1670±271 (n=9) and i6-keto-PGF1α was 1191±209 pg/ml (n=10). By 4 h plasma iTXB2 was 1743±328 pg/ml (n=5), iPGE was 2589±494 pg/ml (n=9) and i6-keto-PGF1α was 4251±984 pg/ml (n=10). UK 37248 pretreatment resulted in a significant (P<0.001) decrease in plasma iTXB2 at 30 min and 4 h to 193±28 pg/ml (n=5) and 421±57 pg/ml (n=5), respectively. Unexpectedly UK 37248 also significantly decreased plasma i6-keto PGF1α at 30 min and 4 h to 360±75 pg/ml (n=10) (P<0.005) and 1920±513 pg/ml (n=10) (P<0.05), respectively. iPGE plasma levels were not significantly changed in the UK 37248-pretreated rats 30 min (2210±370 pg/ml (n=9) or 4 h 3529±1093 pg/ml (n=13) after endotoxin compared to the vehicle-treated rats. 3 UK 37248 significantly (P<0.05) reduced the endotoxin mortality rate at 24 h from 69% (n=13) to 30% (n=13). UK 37248 also reduced splanchnic infarction from 90% (n=20) to 6% (n=16). 4 UK 37248 significantly improved the endotoxin-induced thrombocytopaenia, disseminated intravascular coagulation, hypoglycaemia and lysosomal labilization. 5 We conclude that UK 37248 provides significant beneficial effects in experimental endotoxic shock in the rat.