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  • Three-month subchronic intramuscular toxicity study of rotigotine-loaded microspheres in Cynomolgus monkeys.

Three-month subchronic intramuscular toxicity study of rotigotine-loaded microspheres in Cynomolgus monkeys.

Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association (2012-11-21)
Jingwei Tian, Guangying Du, Liang Ye, Xin Yu, Jianzhao Zhang, Hongbo Wang, Pengfei Yu, Fenghua Fu, Wanhui Liu, Youxin Li, Xiaobo Cen, Xiaolin Guan
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Resomer® RG 505, Poly(D,L-lactide-co-glycolide), ester terminated, Mw 54,000-69,000
Sigma-Aldrich
Rotigotine hydrochloride, ≥98% (HPLC)
Sigma-Aldrich
Resomer® RG 504 H, Poly(D,L-lactide-co-glycolide), acid terminated, lactide:glycolide 50:50, Mw 38,000-54,000
Sigma-Aldrich
Resomer® RG 756 S, Poly(D,L-lactide-co-glycolide), ester terminated, lactide:glycolide 75:25, Mw 76,000-115,000
Sigma-Aldrich
Resomer® RG 858 S, Poly(D,L-lactide-co-glycolide), ester terminated, lactide:glycolide 85:15, Mw 190,000-240,000
Sigma-Aldrich
Resomer® RG 504, Poly(D,L-lactide-co-glycolide), lactide:glycolide 50:50, ester terminated, Mw 38,000-54,000
Sigma-Aldrich
Resomer® RG 503, Poly(D,L-lactide-co-glycolide), lactide:glycolide 50:50, ester terminated, Mw 24,000-38,000
Sigma-Aldrich
Poly(D,L-lactide-co-glycolide), ester terminated, Mw 50,000-75,000
Sigma-Aldrich
Poly(D,L-lactide-co-glycolide), lactide:glycolide 65:35, Mw 40,000-75,000
Sigma-Aldrich
Poly(D,L-lactide-co-glycolide), lactide:glycolide (75:25), mol wt 66,000-107,000
Sigma-Aldrich
Poly(D,L-lactide-co-glycolide), lactide:glycolide (50:50), mol wt 30,000-60,000
Sigma-Aldrich
Resomer® RG 752 H, Poly(D,L-lactide-co-glycolide), acid terminated, lactide:glycolide 75:25, Mw 4,000-15,000
Sigma-Aldrich
Resomer® RG 653 H, Poly(D,L-lactide-co-glycolide), acid terminated, Mw 24,000-38,000
Sigma-Aldrich
Resomer® RG 503 H, Poly(D,L-lactide-co-glycolide), acid terminated, lactide:glycolide 50:50, Mw 24,000-38,000
Sigma-Aldrich
Resomer® RG 502 H, Poly(D,L-lactide-co-glycolide), acid terminated, Mw 7,000-17,000
Sigma-Aldrich
Resomer® RG 502, Poly(D,L-Lactide-co-Glycolide), lactide:glycolide 50:50, ester terminated, Mw 7,000-17,000