Rotigotine polyoxazoline conjugate SER‐214 provides robust and sustained antiparkinsonian benefit

Autor: Tom H. Johnston, Bekir Dizman, David G. Standaert, Michael D. Bentley, Zhihao Fang, Michael Hill, Randall Moreadith, Kunsang Yoon, Rebecca Weimer, Karen L. Eskow Jaunarajs, Jonathan M. Brotchie, Paula Ravenscroft, Tacey X. Viegas
Rok vydání: 2013
Předmět:
Zdroj: Movement Disorders. 28:1675-1682
ISSN: 1531-8257
0885-3185
DOI: 10.1002/mds.25625
Popis: Currently available dopaminergic drugs such as levodopa and dopamine (DA) receptor agonists impart considerable improvement in Parkinson's disease (PD) motor symptoms but often lead to signifi- cant motor complications including "wearing-off" and dyskinesia. Such complications are believed to stem from the pulsatile nature of dopaminergic stimulation with these agents. Continuous dopaminergic drug delivery using polyoxazoline (POZ) polymer conjugation may improve motor symptoms, while avoiding development of side effects. The purposes of the current study are to characterize the in vitro and in vivo pharmacokinetics of POZ conjugation of a U.S. Food and Drug Administration (FDA)-approved DA agonist, rotigotine, and to evaluate their effects in an established rat model of PD. After determination of release profiles of several POZ- conjugated constructs ("fast": SER-212; "moderate": SER-213; and "slow": SER-214) using in vitro hydrolysis, normal male Sprague-Dawley rats were used for determi- nation of the pharmacokinetic profile of both acute and chronic exposure. Finally, a separate group of rats was rendered hemiparkinsonian using intracranial 6- hydroxydopamine (6-OHDA) infusions, treated acutely with POZ-rotigotine, and assessed for rotational behavior and antiparkinsonian benefit using the cylinder test. POZ-rotigotine formulations SER-213 and SER-214 led to substantial pharmacokinetic improvement compared to unconjugated rotigotine. In addition, SER-214 led to antiparkinsonian effects in DA-lesioned rats that per- sisted up to 5 days posttreatment. Repeated weekly dose administration of SER-214 to normal rats for up to 12 weeks demonstrated highly reproducible pharmacoki- netic profiles. The continuous dopaminergic stimulation profile afforded by SER-214 could represent a significant advance in the treatment of PD, with potential to be a via- ble, once-per-week therapy for PD patients.
Databáze: OpenAIRE
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