General pharmacology of recombinant human tumor necrosis factor. 2nd communication: effects on central nervous system functions.
Effects of recombinant human Tumor Necrosis Factor (rHu-TNF, PT-050) administered s.c. and i.v. on the central nervous system were investigated behaviorally and physiologically in different animal species. With i.v. administration at doses of 10(4) U/kg and less, PT-050 produced no significant changes in most of behavioral and physiological tests, except that a transient increase in rectal temperature in dogs occurred with 0.765 x 10(4) U/kg and acetic acid-induced writhing syndrome in mice was inhibited with 10(4) U/kg. Locomotor activity in mice was inhibited after 3 x 10(4) U/kg. With 10(5) U/kg and more, in addition to the above effects, diverse effects were observed as follows: various symptoms were induced in general behavior in mice such as piloerection, catalepsy, lowering of body position, ptosis and pupil dilatation; rectal temperature was increased in rats and decreased in mice; cortical EEG was synchronized in hippocampal theta waves were disturbed in gallamine-immobilized cats. On the other hand, with s.c. administration, the effect on rectal temperature was seen at 10(4) U/kg in dogs and at 10(5) U/kg in rats. Cortical EEG in conscious rabbits was affected with 10(6) U/kg. At higher dose of 10(7) U/kg. PT-050 (s.c.) further influenced locomotor activity, rectal temperature and acetic acid-induced writhing syndrome in mice. However, even with 10(7) U/kg (s.c.), no effect was found in general behavior, rotarod performance and hexobarbital narcosis in mice. Thus, it is concluded that PT-050 has weaker effects on the central nervous system by s.c. route than by i.v. route. From the present findings and the efficacy of PT-050 as TNF, it is suggested that PT-050, when administered intratumorally, may be useful for cancer therapy without severe side effects.
Kurumiya
S
S
Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
Miura
Y
Y
Nakatsuji
K
K
Dodo
M
M
Hori
M
M
Ito
T
T
D000700:Analgesics; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D002415:Cats; D002490:Central Nervous System / Q000187:drug effects*; D004285:Dogs; D004569:Electroencephalography; D005260:Female; D006591:Hexobarbital / Q000494:pharmacology; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D004856:Postural Balance / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D012890:Sleep / Q000187:drug effects; D013045:Species Specificity; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000700:Analgesics; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D006591:Hexobarbital