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Preliminary safety evaluation of a taurocholate‐conjugated low‐molecular‐weight heparin derivative (LHT7): a potent angiogenesis inhibitor
Author(s) -
Alam Farzana,
Chung Seung Woo,
Hwang Seung Rim,
Kim Jiyoung,
Park Jooho,
Moon Hyun Tae,
Byun Youngro
Publication year - 2015
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/jat.2995
Subject(s) - pharmacology , biodistribution , toxicity , chemistry , liver function , acute toxicity , angiogenesis , low molecular weight heparin , kidney , mechanism of action , medicine , heparin , biochemistry , in vitro
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. LD 50 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. Copyright © 2014 John Wiley & Sons, Ltd.