title: Single and repeated intravenous toxicity studies of pamiteplase (genetical recombination) in rats and monkeys.
abstract: Single and repeated intravenous toxicity studies of Pamiteplase (genetical recombination) YM866, a novel recombinant human tissue-type plasminogen activator, were conducted. No animal died from toxic effects of YM866 after single administration to F344 rats, squirrel monkeys and cynomolgus monkeys. Male and female F344 rats were given YM866 intravenously for 4 weeks at doses of 0 (vehicle), 0.1, 0.3 and 1 mg/kg/day. An increase in platelet count, slight decreases in hemoglobin and hematocrit, increases in plasma phospholipids, total cholesterol and total protein, and liver weight were observed at 1.0 mg/kg. Histopathology revealed no changes in any organ except for hemorrhage at the injection sites. These changes recovered after 4 weeks of withdrawal. Male and female squirrel monkeys were given YM866 intravenously for 4 weeks at doses of 0 (saline), 0 (vehicle), 0.1, 0.3 and 1 mg/kg/day. Prolongation of coagulation time at the injection site was observed at 0.3 mg/kg or more. Subcutaneous hemorrhage and a transient decrease in locomotor activity were observed at 1 mg/kg. Prolongation of coagulation time at the injection site was considered to be related to the pharmacological action of YM866. The results show that the approximate single lethal dose of YM866 is more than 60 mg/kg in rats, and more than 10 mg/kg in squirrel monkeys and cynomolgus monkeys. The no-toxic-effect level of YM866 after repeated administration for 4 weeks in rats and squirrel monkeys is considered to be 0.3 mg/kg.
authors.affiliation: Medicinal Safety Laboratories, Yamanouchi Pharmaceutical Co., Ltd., Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Ishikawa
authors.forename: T
authors.initials: T
authors.lastname: Ohata
authors.forename: K
authors.initials: K
authors.lastname: Imamura
authors.forename: M
authors.initials: M
authors.lastname: Iwasaki
authors.forename: T
authors.initials: T
authors.lastname: Sakai
authors.forename: T
authors.initials: T
authors.lastname: Matsuzawa
authors.forename: S
authors.initials: S
authors.lastname: Okazaki
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001774:Blood Chemical Analysis; D001777:Blood Coagulation / Q000187:drug effects; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects; D001798:Blood Proteins / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D006400:Hematocrit; D006454:Hemoglobins / Q000378:metabolism; D006470:Hemorrhage / Q000139:chemically induced; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010743:Phospholipids / Q000097:blood; D010976:Platelet Count / Q000187:drug effects; D011517:Prothrombin Time; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000633:toxicity; D012453:Saimiri; D013045:Species Specificity; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000633:toxicity*; D014556:Urine / Q000737:chemistry
chemical_list: D015415:Biomarkers; D001798:Blood Proteins; D006454:Hemoglobins; D010743:Phospholipids; D011994:Recombinant Proteins; D002784:Cholesterol; D010959:Tissue Plasminogen Activator; C085027:pamiteplase