title: A 26-week repeated-dose toxicity study of allisartan isoproxil in Sprague-Dawley rats.
abstract: Allisartan isoproxil (ALS-3) is a selective, nonpeptide blocker of the angiotensin II type 1 receptor. It is a new antihypertensive drug under development with a novel chemical structure. The aim of this study was to evaluate the potential toxicity of ALS-3 in Sprague-Dawley rats. Animals were orally administered either vehicle or ALS-3 at doses of 20, 80 and 320 mg/kg once-daily for 26 weeks, followed by a 6-week recovery period. Toxicity was assessed by mortality, clinical signs, body weight, food consumption, hematology, coagulation, serum chemistry, gross necropsy, organ weights and microscopic examination. Decreased body-weight gain was noted at 320 mg/kg/day in both sexes as well as at the 80-mg/kg/day dose in females. Food consumption was decreased at all doses in males and at 80- and 320-mg/kg/day doses in females. Decreased erythrocyte parameters (erythrocyte count, hemoglobin and hematocrit) were observed in males receiving 320 mg/kg/day. Elevated urea nitrogen (BUN), increased kidney weight, decreased heart weight and exacerbation of chronic progressive nephropathy (CPN) severity were all observed in males at 80 and 320 mg/kg/day. However, only an exacerbated incidence of CPN was observed in females at 320 mg/kg/day. All changes were reversed after the 6-week recovery period, except BUN and CPN. Based on these results, we concluded that a dose of 20 mg/kg/day was the no observed adverse effect level. The toxicity target organ was the kidney. Males were more affected than females.
authors.affiliation: Shanghai JiaoTong University School of Medicine, Shanghai, China.
authors.forename: Yongzhen
authors.initials: Y
authors.lastname: Liu
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Yumei
authors.initials: Y
authors.lastname: Cheng
authors.forename: Jingjun
authors.initials: J
authors.lastname: Sun
authors.forename: Junwen
authors.initials: J
authors.lastname: Qiao
authors.forename: Henglei
authors.initials: H
authors.lastname: Lu
authors.forename: Liang
authors.initials: L
authors.lastname: Zhu
authors.forename: Likun
authors.initials: L
authors.lastname: Gong
authors.forename: Jin
authors.initials: J
authors.lastname: Ren
mesh_terms: D000284:Administration, Oral; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000633:toxicity*; D001713:Biphenyl Compounds / Q000633:toxicity*; D001774:Blood Chemical Analysis; D001780:Blood Coagulation Tests / Q000379:methods; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects; D005260:Female; D006321:Heart / Q000187:drug effects; D007093:Imidazoles / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; C587132:allisartan isoproxil