title: Safety studies on intravenous infusion of a potent angiogenesis inhibitor: taurocholate-conjugated low molecular weight heparin derivative LHT7 in preclinical models.
abstract: BACKGROUND
  As a class of angiogenesis inhibitors, heparin conjugates have shown significant effectiveness in several studies.
  
  
  OBJECTIVE
  The purpose of our current study is to evaluate the effectiveness and safety of infusing the conjugate of low molecular weight heparin and taurocholate (LHT7), which has been developed as a potent angiogenesis inhibitor.
  
  
  METHODS
  To evaluate its safety, the method of intravenous infusion was compared with its i.v. bolus administration. Intravenous infusion was administered at a rate of 400 μl/min/kg of body weight for 30 min. Pharmacokinetic (PK) analysis, organ accumulation, and plasma concentration profiles of LHT7 were measured. The anticancer effect of LHT7 was evaluated in murine and human xenograft models, and preclinical studies were performed in SD rats and beagle dogs.
  
  
  RESULTS
  The results of the PK studies showed reduced organ accumulation in mice and the AUC(0-96 h) (area under the curve) was increased up to 1485 ± 125 h × μg/ml. The efficacy, at dose 1 mg/kg/2 d was higher for i.v. infusion than for i.v. bolus administration in both murine and human cancer models. The preclinical studies showed the safety dose of LHT7 is less than 20 mg/kg in SD rats and in the next safety analysis in beagle dogs showed that there were no organ-specific adverse effects in higher doses, such as, 12 mg/kg. LHT7 showed sustained effects with minimized adverse events when administered through i.v. infusion.
  
  
  CONCLUSIONS
  LHT7 (i.v. infusion) could be safely used for further clinical development as a multi-targeting anti-angiogenic agent.
authors.affiliation: a Research Institute of Pharmaceutical Science, College of Pharmacy, Seoul National University , Seoul , South Korea ;
authors.forename: Farzana
authors.initials: F
authors.lastname: Alam
authors.affiliation: b College of Pharmacy, Chosun University , Gwangju , South Korea ;
authors.forename: Seung Rim
authors.initials: SR
authors.lastname: Hwang
authors.affiliation: c Center for Theragonosis, Biomedical Research Institute, Korea Institute of Science and Technology , Wolgog, Seoul , South Korea ;
authors.forename: Taslim A
authors.initials: TA
authors.lastname: Al-Hilal
authors.affiliation: a Research Institute of Pharmaceutical Science, College of Pharmacy, Seoul National University , Seoul , South Korea ;
authors.forename: Seung Woo
authors.initials: SW
authors.lastname: Chung
authors.affiliation: d ChemOn Inc., Bio-Research Center , Gyeonggi-Do , South Korea ;
authors.forename: Hak-Soo
authors.initials: HS
authors.lastname: Kim
authors.affiliation: d ChemOn Inc., Bio-Research Center , Gyeonggi-Do , South Korea ;
authors.forename: Boo-Hyun
authors.initials: BH
authors.lastname: Kang
authors.affiliation: d ChemOn Inc., Bio-Research Center , Gyeonggi-Do , South Korea ;
authors.forename: Hu-Song
authors.initials: HS
authors.lastname: Zhang
authors.affiliation: d ChemOn Inc., Bio-Research Center , Gyeonggi-Do , South Korea ;
authors.forename: Seo-Ho
authors.initials: SH
authors.lastname: Shin
authors.affiliation: d ChemOn Inc., Bio-Research Center , Gyeonggi-Do , South Korea ;
authors.forename: Joo-Young
authors.initials: JY
authors.lastname: Lee
authors.affiliation: d ChemOn Inc., Bio-Research Center , Gyeonggi-Do , South Korea ;
authors.forename: Min-Soo
authors.initials: MS
authors.lastname: Kang
authors.affiliation: d ChemOn Inc., Bio-Research Center , Gyeonggi-Do , South Korea ;
authors.forename: Geum-Hee
authors.initials: GH
authors.lastname: Kwon
authors.affiliation: e Mediplex Corp , Seoul , South Korea ;
authors.forename: Ok-Cheol
authors.initials: OC
authors.lastname: Jeon
authors.affiliation: f Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology , Seoul , South Korea ;|g Department of Otolaryngology , Asan Medical Center, College of Medicine, University of Ulsan , Seoul , South Korea.
authors.forename: Sang Yoon
authors.initials: SY
authors.lastname: Kim
authors.affiliation: a Research Institute of Pharmaceutical Science, College of Pharmacy, Seoul National University , Seoul , South Korea ;|e Mediplex Corp , Seoul , South Korea ;
authors.forename: Youngro
authors.initials: Y
authors.lastname: Byun
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects*; D000818:Animals; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage* / Q000009:adverse effects*; D006801:Humans; D007262:Infusions, Intravenous / Q000379:methods; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D051381:Rats; D017207:Rats, Sprague-Dawley; D012449:Safety; D013656:Taurocholic Acid / Q000008:administration & dosage* / Q000009:adverse effects*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D020533:Angiogenesis Inhibitors; D006495:Heparin, Low-Molecular-Weight; D013656:Taurocholic Acid
keywords: Angiogenesis inhibitor; intravenous infusion; low molecular weight taurocholate conjugated heparin derivative; preclinical study; safety