The induction of interleukin-6 (IL-6) and colony-stimulating factors (CSFs) by FK565 and its thrombopoietic activity following in vivo administration.
The induction of macrophage colony-stimulating factor (M-CSF) in monkey plasma following administration of FK565 was observed within 2 h of injection peaked at 4 h, and remained high after 24 h. Interleukin-6 (IL-6) and M-CSF levels increased in monkeys treated with FK565, even at doses as low as 0.01 mg/kg. Granulocyte CSF (G-CSF) levels increased slightly following a dose of 1 mg/kg, but granulocyte macrophage CSF (GM-CSF) was not detected at any doses of FK565 studied. To examine the thrombopoietic activity of FK565 in vivo, single doses of drug (0.01, 0.1 or 1.0 mg/kg) were administered i.v. to cynomolgus monkeys or normal mice on day 0. The promotes platelet (PLT) count after FK565 injection decreased transiently on days 1 and 2, and then increased in a dose-dependent manner on day 5 and was still high on day 14. The experiment using anti-PLT antibody showed that the increased PLT count was not simply due to a rebound phenomenon after the transient decrease in PLT. The effect of i.v. FK565 was studied in mice myelosuppressed with a single dose of mitomycin C (MMC) (5.6 mg/kg). The fall in PLT count was suppressed on day 7 by 0.1 and 1.0 mg/kg FK565. Although intact cells or tissues are necessary for an increase in PLT following FK565 treatment, FK565 suppressed the impaired hematopoietic function seen after chemotherapy. FK565 is proposed as a drug to restore reduced neutrophil and platelet counts found in AIDS or cancer therapy.
Maeda
M
M
Product Development Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Suzuki
S
S
Ohtsuka
K
K
Satoh
S
S
Nishigaki
F
F
Shimomura
K
K
Imai
Y
Y
Niwa
M
M
Kohsaka
M
M
D000818:Animals; D000911:Antibodies, Monoclonal; D001792:Blood Platelets / Q000187:drug effects*; D003115:Colony-Stimulating Factors / Q000097:blood*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000097:blood; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000097:blood; D006410:Hematopoiesis / Q000187:drug effects*; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D008252:Macaca fascicularis; D016173:Macrophage Colony-Stimulating Factor / Q000097:blood; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D010976:Platelet Count / Q000187:drug effects; D011994:Recombinant Proteins / Q000097:blood
D000911:Antibodies, Monoclonal; D003115:Colony-Stimulating Factors; D015850:Interleukin-6; D009842:Oligopeptides; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C039537:heptanoyl-gamma-D-glutamyl-L-meso-diaminopimelyl-D-alanine