title: Safety evaluation of recombinant staphylokinase in rhesus monkeys.
abstract: Recombinant staphylokinase (rSTAR) is a profibrinolytic agent of bacterial origin. The objective of this study was to assess the toxicity of rSTAR administered with bolus intravenous infusion in rhesus monkeys (2/sex/group) at the dosages of 0, 4, 14, and 49 mg/kg/day for 2 weeks. The clinical signs were thickening of the skin in all animals and mild hematoma formation in three dosage groups at the injection sites. There were no effects on body weight, absolute or relative organ weights, ophthalmology, or electrocardiogram. Urinalysis indicated that 2 monkeys in 14 or 49 mg/kg/day group developed proteinuria and mild hematuria. Increases in serum BUN levels (14 and 49 mg/kg/day), ALT activity, and bilirubin levels (49 mg/kg/day), and decreases in red blood cell counts, hemoglobin concentrations and Hct values (49 mg/kg/day) were observed at week 2. Significant prolongtion of APTT, PT, and TT (14 and 49 mg/kg/day), and decreases in circulating plasminogen levels (3 treatment groups) were noted. Dose-dependent increases in the titers of anti-rSTAR antibodies and neutralizing rSTAR activity were observed in the three treated groups. Increased neutralizing rSTAR activity diminished the phamacologic effects of rSTAR (ie, prolonged APTT, PT, and TT approaching baseline levels at week 2). Histopathological findings included hemorrhage, and perivascular inflammatory cell infiltration at the injection sites, heptocellular degeneration characterized as cytoplasmic eosinophilia, vacuolation and condensed nuclei (49 mg/kg/day), effusion of RBCs and plasma within some Bowman's capsules and hyaline casts within the lumen of some renal tubules in the kidneys (14 and 49 mg/day/kg), and mild to moderate megakaryocyte hypoplasia with varying levels of pyknotic nuclei at all dose levels. Immune deposits in glomeruli in the kidneys from the three treated groups were detected. These changes were reversible following a 4-week recovery period. In the present preclinical evaluation of toxicity in monkeys, rSTAR is well toleratte at doses up to 49 mg/kg/day. The toxic target organs are the liver, kidney, and bone marrow.
authors.affiliation: Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, People's Republic of China. luqj@nic.bmi.ac.cn
authors.forename: Qiujun
authors.initials: Q
authors.lastname: Lu
authors.forename: Yuanmin
authors.initials: Y
authors.lastname: Li
authors.forename: Liqing
authors.initials: L
authors.lastname: Wen
authors.forename: Shaoming
authors.initials: S
authors.lastname: Guo
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Chen
authors.forename: Weijing
authors.initials: W
authors.lastname: Liu
authors.forename: Yue
authors.initials: Y
authors.lastname: Gao
authors.forename: Lingmao
authors.initials: L
authors.lastname: Ding
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D001772:Blood Cell Count; D001777:Blood Coagulation / Q000187:drug effects; D001806:Blood Urea Nitrogen; D001835:Body Weight / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004562:Electrocardiography; D004926:Escherichia coli / Q000201:enzymology; D005123:Eye / Q000187:drug effects; D007262:Infusions, Intravenous; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008253:Macaca mulatta; D020714:Maximum Tolerated Dose; D008666:Metalloendopeptidases / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D010960:Plasminogen Activators / Q000633:toxicity*; D011994:Recombinant Proteins / Q000633:toxicity*; D012867:Skin / Q000187:drug effects; D016482:Urinalysis
chemical_list: D011994:Recombinant Proteins; D000410:Alanine Transaminase; D010960:Plasminogen Activators; D008666:Metalloendopeptidases; C022653:auR protein, Staphylococcus aureus