title: Evaluation of safety of iridoids rich fraction from Valeriana jatamansi Jones: Acute and sub-chronic toxicity study in mice and rats.
abstract: BACKGROUND
  Valeriana jatamansi Jones named Zhizhuxiang in China is one of the most popular traditional medicine for varied ailments related to malaise, abdominal distention, insomnia, and rheumatism.
  
  
  OBJECTIVE
  Evaluate the safety of iridoids rich fraction from V. jatamansi Jones (IRFV) and to provide data for clinical application.
  
  
  METHODS
  The acute and sub-chronic toxicity of IRFV were investigated by employing established methods. The acute toxicity study was conducted through oral administration of a single dose (3,200 mg/kg body weight) of IRFV to adult mice. The vehicle used for dilution of the IRFV was a mixture of 0.5% CMC-Na and 99.5% water. The weight, diet, toxic reaction, and death after 14 days were observed. In the sub-chronic toxicity study, low doses (240 mg/kg bw), middle doses (960 mg/kg bw), and high doses (1,200 mg/kg bw) of IRFV were administered daily to adult rats for 6 days a week (except Sunday) for 3 months. The general behavior of the rats was observed and recorded daily. The weight and food consumption of rats were tested weekly. The effect on organs, the hematological and blood biochemical parameters, and the histopathology were assessed after 1.5 months (five males and five females) and after 3 months (10 males and 10 females).The remaining 10 rats (five males and five females) in each group were fed for 2 weeks to observe reversible and delayed toxicity after the medicine was administered.
  
  
  RESULTS
  In the acute toxicity study, no significant difference was found in the body weight of the mice in the control group and those in the drug group (p>0.05). The maximum tolerated dose of IRFV on mice was 3,200 mg/kg, which is 2666 times of the clinical adult daily dose. In the sub-chronic toxicity study on rats, the daily single oral doses of the IRFV did not result in death nor affected the general behavior, including appearance, activities, discharge, and waste at all tested doses. Moreover, no significant difference was found (p>0.05) between the body weights of the rats from the drug groups and those from the control group. Food consumption was significantly affected (p<0.05) only in the first 3 weeks. No statistically significant differences (p>0.05) were observed in the hematological and blood biochemical parameters, and no abnormality of other organs were noted in both gross and histopathological examinations, except several animal transients (p<0.05) or spontaneous lesions (abnormality).
  
  
  CONCLUSIONS
  IRFV is extremely safe in the usual clinical dose, and may not have any single dose toxicity. The lethal dose with 50% mortality rate (LD50) on mice is over 2,000 mg/kg bw. The no-observed adverse effects level is 1,200 mg/kg/day for rats. No direct correlation was found between the hematology, blood biochemical indexes, and organ coefficient of tested rats and the toxicity of IRFV.
authors.affiliation: School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China.
authors.forename: Keke
authors.initials: K
authors.lastname: Xu
authors.affiliation: School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Lin
authors.affiliation: School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China.
authors.forename: Ruitong
authors.initials: R
authors.lastname: Zhang
authors.affiliation: School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Lan
authors.affiliation: School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China.
authors.forename: Chaoyong
authors.initials: C
authors.lastname: Chen
authors.affiliation: School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Li
authors.affiliation: School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China.
authors.forename: Changying
authors.initials: C
authors.lastname: Zuo
authors.affiliation: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Chen
authors.affiliation: School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
authors.forename: Tiane
authors.initials: T
authors.lastname: Zhang
authors.affiliation: School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China. Electronic address: yzhiy@swjtu.edu.cn.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Yan
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D039823:Iridoids / Q000008:administration & dosage / Q000302:isolation & purification / Q000633:toxicity*; D008297:Male; D020714:Maximum Tolerated Dose; D008516:Medicine, Chinese Traditional; D051379:Mice; D019055:No-Observed-Adverse-Effect Level; D010936:Plant Extracts / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D023382:Toxicity Tests, Acute; D059550:Toxicity Tests, Subchronic; D014632:Valerian / Q000737:chemistry*
chemical_list: D039823:Iridoids; D010936:Plant Extracts
keywords: Acute toxicity; Iridoids rich fraction; Mice; Rat; Sub-chronic toxicity; Valeriana jatamansi Jones