General pharmacology of recombinant human tumor necrosis factor. 1st communication: effects on cardiovascular, gastrointestinal, renal and blood functions

Abstract

The effects of recombinant human Tumor Necrosis Factor (rHu-TNF, PT-050), an antitumor agent, on the cardiovascular, gastrointestinal, renal and blood functions were examined in experimental animals. 1. PT-050 at 10(5) U/kg i.v. did not affect blood pressure and blood flow in anesthetized dogs. However, these were decreased 2-3 h after i.v. injection of 10(6) U/kg. A sustained decrease in blood pressure was seen in conscious dogs. PT-050 decreased systolic blood pressure and increased heart rate with a peak at 5-7 h after administration of 10 micrograms/kg (2.55 x 10(4) U/kg) i.v. and 10(5) U/kg s.c. PT-050 was without effect on perfusion volume in rabbit ear vessel preparations. 2. PT-050 enhanced gastric emptying in rats and intestinal charcoal meal propulsion in mice at 10(6) and 10(7) U/kg s.c., respectively. It decreased gastric juice volume and acid content with an increase of gastric juice pH in pyrolus ligated rats at 10(6) U/kg s.c. 3. PT-050 caused diarrhea at 10(5) U/kg i.v. in mice, while at 10(7) U/kg s.c., it did not exert the effect. 4. PT-050 increased urine volume and Na+ excretion at 3 x 10(3) U/kg i.v. and 10(5) U/kg s.c. in saline-loaded rats. 5. PT-050 decreased platelet counts at 10(5) U/kg i.v., depressed platelet aggregation responses to collagen and ADP at 10(6) U/kg i.v., and prolonged APTT and PT at 3 x 10(5) U/kg i.v. in rats, although it neither affected platelet aggregation nor blood coagulation in vitro. PT-050 neither affected platelet counts at 10(5) U/kg s.c., nor platelet aggregation at 10(7) U/kg s.c.(ABSTRACT TRUNCATED AT 250 WORDS)