General pharmacology of recombinant human tumor necrosis factor. 1st communication: effects on cardiovascular, gastrointestinal, renal and blood functions.
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)
Nakatsuji
K
K
Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
Kii
Y
Y
Fujitani
B
B
Ito
T
T
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003967:Diarrhea / Q000139:chemically induced; D004064:Digestive System / Q000187:drug effects*; D004285:Dogs; D004562:Electrocardiography; D005260:Female; D005746:Gastric Emptying / Q000187:drug effects; D005772:Gastrointestinal Transit / Q000187:drug effects; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D007668:Kidney / Q000187:drug effects*; D008297:Male; D051379:Mice; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D010976:Platelet Count; D011817:Rabbits; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects; D012119:Respiration / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D010975:Platelet Aggregation Inhibitors; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha