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Cited by 15Parkinson's Disease Mechanisms and TreatmentsImmunotoxicology and immune responsesAdvanced Drug Delivery Systems

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

Tian, Jingwei, Du, Guangying, Ye, Liang, Yu, Xin, Zhang, Jianzhao, Wang, Hongbo, Yu, Pengfei, Fu, Fenghua +4 more·2013·Food and Chemical Toxicology
DOI 10.1016/j.fct.2012.11.010
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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.

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  • Chronic administration of rotigotine-loaded PLGA-MS in monkey and SD rats showed sustained release behavior accompanied by better safety.

    “Other investigators also confirmed that chronic administration of rotigotine-loaded PLGA-MS in monkey and SD rats showed sustained release behavior accompanied by better safety.123,124”

    From Targeted therapy in chronic diseases using nanomaterial-based drug delivery vehicles (2019) · cites this paper as [124]

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Authors
Tian, J., Du, G., Ye, L., Yu, X., Zhang, J., Wang, H., Yu, P., Fu, F., Liu, W., Li, Y., Cen, X., & Guan, X.
Affiliations
Yantai University (CN)
Corresponding author
Ye, Liang
ORCID
Venue
Food and Chemical Toxicology
Publisher
Elsevier BV
Published
2013-02
Volume
52
Pages
143-152
ISSN
0278-6915 (ISSN-L)
DOI
10.1016/j.fct.2012.11.010
OpenAlex
W1993392143
Cited by
15
References
27
Citations by year
2025: 2 · 2024: 3 · 2023: 1 · 2022: 1 · 2021: 2 · 2019: 1 · 2017: 2 · 2016: 1 · 2015: 1 · 2013: 1
FWCI
0.42
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Food and Chemical Toxicology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
Keywords
rotigotine, subchronic toxicity, continuous dopaminergic stimulation, Parkinson's disease, dopamine agonists, poly(lactic-co-glycolic acid), sustained drug release, foreign body reaction, foreign body granuloma, hyperactivity, stereotypy, prolactin, carboxymethylcellulose sodium, no-observed-adverse-effect level, Macaca fascicularis
MeSH terms
Animals, Atrophy, Blood Pressure, Body Temperature, Body Weight, Bone Marrow, Eating, Electrocardiography, Female, Injections, Intramuscular, Macaca fascicularis, Male, Microspheres, Mortality, Organ Size, Parkinson Disease, Polyglactin 910, Prolactin, Pulmonary Embolism, Tetrahydronaphthalenes, Thiophenes, Thymus Gland, Dopamine Agonists, Toxicity Tests, Subchronic

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