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.
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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 [123]
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- Authors
- Ye, L., Guan, X., Tian, J., Zhang, J., Du, G., Yu, X., Yu, P., Cen, X., Liu, W., & Li, Y.
- Affiliations
- Yantai University (CN)
- Venue
- Food and Chemical Toxicology
- Publisher
- Elsevier BV
- Published
- 2013-06
- Volume
- 56
- Pages
- 81-92
- ISSN
- 0278-6915 (ISSN-L)
- OpenAlex
- W2030053567
- Cited by
- 14
- References
- 43
- Citations by year
- 2025: 3 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 1 · 2019: 2 · 2016: 1 · 2015: 1 · 2014: 1
- FWCI
- 0.63
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Food and Chemical Toxicology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Keywords
- rotigotine, subchronic toxicity, continuous dopaminergic stimulation, Parkinson's disease, dopamine agonists, sustained drug release, poly(lactic-co-glycolic acid), foreign body reaction, carboxymethylcellulose sodium, hyperactivity, stereotypy, prolactin, liver enzymes, pulmonary embolism, no-observed-adverse-effect level
- MeSH terms
- Alanine Transaminase, Animals, Aspartate Aminotransferases, Body Weight, Dose-Response Relationship, Drug, Female, Injections, Intramuscular, Male, Microspheres, Neutrophils, Organ Size, Ovary, Parkinson Disease, Prolactin, Tetrahydronaphthalenes, Thiophenes, Rats, Sprague-Dawley, Dopamine Agonists, No-Observed-Adverse-Effect Level, Rats, Toxicity Tests, Subchronic
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