title: Preliminary safety evaluation of a taurocholate-conjugated low-molecular-weight heparin derivative (LHT7): a potent angiogenesis inhibitor.
abstract: In our previous studies, taurocholic acid (TA)-conjugated low-molecular-weight heparin derivative (LHT7) has been proven to be a potent anti-angiogenic agent by demonstrated successful blockage capability of vascular endothelial growth factors (VEGF). Preliminary safety evaluations were conducted based on its mechanism of action and chemical behavior. For this purpose, acute toxicity study, and hematological and serological evaluations were carried out. Additionally, in order to evaluate mechanism-related side effects, both blood pressure and the occurrence of proteinuria were measured using a treatment regime of multiple high doses of LHT7 in a biodistribution study. LD50 values for LHT7 in female and male mice were 56.9 and 64.7 mg kg(-1) doses, respectively. There were no vital fluctuations in the serological and hematological parameters, except for the elevated levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) at 100 and 200 mg kg(-1) doses of LHT7, representing vital changes in the liver function. Moreover, the results of mechanism-related studies showed that blood pressure at 50 mg kg(-1) did not change but showed elevated levels of protein in urine. In the biodistribution study, a slight accumulation of LHT7 in the kidney and the liver were observed at the 50 mg kg(-1) repeated dose owing to the presence of bile acid. No fatal damage was observed in this study; most observations were related to the chemical composition or the mechanism of action of the material.
authors.affiliation: Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National University, Seoul, 151-742, South Korea.
authors.forename: Farzana
authors.initials: F
authors.lastname: Alam
authors.forename: Seung Woo
authors.initials: SW
authors.lastname: Chung
authors.forename: Seung Rim
authors.initials: SR
authors.lastname: Hwang
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Jooho
authors.initials: J
authors.lastname: Park
authors.forename: Hyun Tae
authors.initials: HT
authors.lastname: Moon
authors.forename: Youngro
authors.initials: Y
authors.lastname: Byun
mesh_terms: D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D006495:Heparin, Low-Molecular-Weight / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007928:Lethal Dose 50; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008111:Liver Function Tests; D008297:Male; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D009929:Organ Size / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D013656:Taurocholic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D014018:Tissue Distribution; D023382:Toxicity Tests, Acute; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; D006495:Heparin, Low-Molecular-Weight; C580866:LHT7 compound; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D013656:Taurocholic Acid
keywords: angiogenesis inhibitor; low-molecular-weight heparin; preclinical study; taurocholate; vascular endothelial growth factors