General pharmacology of recombinant human tumor necrosis factor. 1st communication: effects on cardiovascular, gastrointestinal, renal and blood functions
Nakatsuji, K.; Kii, Y.; Fujitani, B.; Ito, T.
Arzneimittel-Forschung 40(2 Part 1): 218-225
1990
ISSN/ISBN: 0004-4172 PMID: 2334464 Document Number: 355342
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 t 105 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 106 U/kg. A sustained decrease in blood pressure was seen in conscious dogs. PT-50 decreased systolic blood pressure and increased heart rate with a peak at 5-7 h after administration of 10 .mu.g/kg (2.5 .times. 104 U/kg) i.v. and 105 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 105 and 107 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 106 U/kg s.c. 3. PT-050 caused diarrhea at 105 U/kg i.v. in mice, while at 107 U/kg s.c., it did not exert the effect. 4. PT-050 increased urine volume and Na+ excretion at 3 .times. 103 U/kg i.v. and 105 U/kg s.c. in saline-loaded rats. 5. PT-050 decreased platelet counts at 105 U/kg i.v., depressed platelet aggregation responses to collagen and ADP at 106 U/kg i.v., and prolonged APTT and PT at 3 .times. 105 U/kg i.v. in rats, although it neither affected platelet aggregation nor blood coagulation in vitro. PT-050 neither affected platelet counts at 105 U/kg s.c., nor platelet ggregation at 107 U/kg s.c. From these results, it is indicated that s.c. administration of PT-050 exterts far less effects on the cardiovascular gastrointestinal, renal and blood functions than i.v. administration does. Intratumorally administered PT-050, when used clinically, it is expected to be an antitumor agent with less adverse effects.