title: Three-month subchronic intramuscular toxicity study of rotigotine-loaded microspheres in SD rats.
abstract: Continuous dopaminergic stimulation (CDS) has been an important strategy of drug development for the treatment of Parkinson's disease (PD). Rotigotine is a non-ergoline D3/D2/D1 dopamine agonist for treating PD. As a new treatment option for CDS, rotigotine-loaded microspheres (RoMS), a long-acting sustained-release microspheres for injection with poly(lactide-co-glycolide) as drug carrier, are now being evaluated in clinical trial. In this study, subchronic toxicity of RoMS in SD rats has been characterized via intramuscular administration with RoMS (0-240 mg/kg/week) on a consecutive weekly dosing schedule for 3 months followed by 1-month recovery period. The No Observed Adverse Effect Level (NOAEL) was 45 mg/kg/week. One male at 240 mg/kg died from an extensive pulmonary embolism. The major toxicological effects were associated with the dopamine agonist-related pharmacodynamic properties of rotigotine (e.g. hyperactivity and stereotype, enlarged ovary, sporadic gastric mucous membrane lesions, decreased body weight, food consumption and prolactin, and increased mononuclear cell, neutrophil granulocyte, aspartate aminotransferase and alanine aminotransferase) and foreign body removal reaction induced by poly(lactide-co-glycolide) and carboxymethycellulose sodium. At the end of recovery period, all findings had recovered to a normal level or to a certain degree except foreign body reaction at injection sites. RoMS has exhibited high safety on SD rats.
authors: School of Pharmacy, Yantai University & State Key Laboratory of Long-acting and Targeting Drug Delivery Technologies, Yantai, Shandong 264003, PR China. yeliang@luye.cn
authors: Liang
authors: L
authors: Ye
authors: Xiaolin
authors: X
authors: Guan
authors: Jingwei
authors: J
authors: Tian
authors: Jianzhao
authors: J
authors: Zhang
authors: Guangying
authors: G
authors: Du
authors: Xin
authors: X
authors: Yu
authors: Pengfei
authors: P
authors: Yu
authors: Xiaobo
authors: X
authors: Cen
authors: Wanhui
authors: W
authors: Liu
authors: Youxin
authors: Y
authors: Li
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001835:Body Weight / Q000187:drug effects; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007273:Injections, Intramuscular; D008297:Male; D008863:Microspheres; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D019055:No-Observed-Adverse-Effect Level; D009929:Organ Size / Q000187:drug effects; D010053:Ovary / Q000187:drug effects / Q000378:metabolism; D010300:Parkinson Disease / Q000188:drug therapy; D011388:Prolactin / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000633:toxicity*; D013876:Thiophenes / Q000008:administration & dosage / Q000633:toxicity*; D059550:Toxicity Tests, Subchronic
chemical_list: D018491:Dopamine Agonists; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; C047508:rotigotine; D011388:Prolactin; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase