title: Three-month subchronic intramuscular toxicity study of rotigotine-loaded microspheres in Cynomolgus monkeys.
abstract: Continuous dopaminergic stimulation (CDS) is an important drug development strategy in the treatment of Parkinson's disease (PD). Rotigotine is a non-ergoline D(3)/D(2)/D(1) dopamine receptor agonist for treating PD. As a new treatment option for CDS, rotigotine-loaded microspheres (RoMS), long-acting sustained-release microspheres with poly(lactide-co-glycolide) as drug carrier, are now being evaluated in clinical trial. In the present study, the subchronic toxicity in Cynomolgus monkeys has been characterized via intramuscular administration with RoMS at 0, 10, 40 and 160 mg/kg, weekly for 3 months with a 1-month recovery period. The NOAEL was 10 mg/kg/week. One male at 160 mg/kg died from an extensive pulmonary embolism. The major toxicological effects were associated with dopamine agonist-related pharmacodynamic properties of rotigotine (e.g., hyperactivity and stereotype, decreased serum prolactin level) and foreign body removal reaction induced by poly(lactide-co-glycolide) and carboxymethycellulose sodium (e.g., increased mononuclear cells and neutrophils, thymus atrophy and vacuolar degeneration of adrenal cortex, foreign body granuloma with foam cells accumulation at injection sites and foam cells accumulation in spleen and multiple lymph sinuses). At the end of recovery period, above findings recovered to a normal level or to a certain degree except vacuolar degeneration of adrenal gland. RoMS has exhibited high safety on monkeys.
authors.affiliation: School of Pharmacy, Yantai University & State Key Laboratory of Long-acting and Targeting Drug Delivery Technologies, Yantai, Shandong 264003, PR China. project0081@hotmail.com
authors.forename: Jingwei
authors.initials: J
authors.lastname: Tian
authors.forename: Guangying
authors.initials: G
authors.lastname: Du
authors.forename: Liang
authors.initials: L
authors.lastname: Ye
authors.forename: Xin
authors.initials: X
authors.lastname: Yu
authors.forename: Jianzhao
authors.initials: J
authors.lastname: Zhang
authors.forename: Hongbo
authors.initials: H
authors.lastname: Wang
authors.forename: Pengfei
authors.initials: P
authors.lastname: Yu
authors.forename: Fenghua
authors.initials: F
authors.lastname: Fu
authors.forename: Wanhui
authors.initials: W
authors.lastname: Liu
authors.forename: Youxin
authors.initials: Y
authors.lastname: Li
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Cen
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Guan
mesh_terms: D000818:Animals; D001284:Atrophy / Q000139:chemically induced; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects; D018491:Dopamine Agonists / Q000008:administration & dosage* / Q000633:toxicity*; D004435:Eating / Q000187:drug effects; D004562:Electrocardiography; D005260:Female; D007273:Injections, Intramuscular; D008252:Macaca fascicularis; D008297:Male; D008863:Microspheres; D009026:Mortality; D009929:Organ Size / Q000187:drug effects; D010300:Parkinson Disease / Q000188:drug therapy; D011098:Polyglactin 910 / Q000008:administration & dosage; D011388:Prolactin / Q000097:blood; D011655:Pulmonary Embolism / Q000139:chemically induced; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage* / Q000633:toxicity*; D013876:Thiophenes / Q000008:administration & dosage* / Q000633:toxicity*; D013950:Thymus Gland / Q000187:drug effects / Q000473:pathology; D059550:Toxicity Tests, Subchronic / Q000379:methods*
chemical_list: D018491:Dopamine Agonists; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; D011098:Polyglactin 910; C047508:rotigotine; D011388:Prolactin