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

摘要: 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 complications including "wearing-off" dyskinesia. Such are believed stem from the pulsatile nature of stimulation with these agents. Continuous drug delivery using polyoxazoline (POZ) polymer conjugation may improve symptoms, while avoiding development side effects. The purposes current study characterize vitro vivo pharmacokinetics POZ a U.S. Food Drug Administration (FDA)-approved DA agonist, rotigotine, evaluate their effects an established rat model PD. After determination release profiles several POZ- conjugated constructs ("fast": SER-212; "moderate": SER-213; "slow": SER-214) hydrolysis, normal male Sprague-Dawley rats were used for determi- nation pharmacokinetic profile both acute chronic exposure. Finally, separate group was rendered hemiparkinsonian intracranial 6- hydroxydopamine (6-OHDA) infusions, treated acutely POZ-rotigotine, assessed rotational behavior antiparkinsonian benefit cylinder test. POZ-rotigotine formulations SER-213 SER-214 led substantial compared unconjugated rotigotine. In addition, DA-lesioned that per- sisted up 5 days posttreatment. Repeated weekly dose administration 12 weeks demonstrated highly reproducible pharmacoki- netic profiles. continuous afforded by could represent significant advance treatment PD, potential be via- ble, once-per-week therapy PD patients.