Randomized, blind, controlled trial of transdermal rotigotine in early Parkinson disease

Watts, R. L.; Jankovic, Joseph; Waters, Cheryl; Rajput, Ali H.; Boroojerdi, Babak; Rao, Jayaraman

doi:10.1212/01.wnl.0000252355.79284.22

Cited by 234 publications

(144 citation statements)

References 17 publications

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“…Rotigotine was chosen as the candidate molecule for development since it is one of the most potent D2/D3 non-ergot agonists currently used clinically with proven safety and efficacy records in PD patients. 17,19,28 Rotigotine has essentially no oral bioavailability and is currently administered through the use of a daily transdermal patch. However, the patch often results in skin reactions and may fall off prematurely, leading to issues with patient compliance.…”

Section: Discussionmentioning

confidence: 99%

“…16 A transdermal system has been developed to provide continuous delivery of the dopamine agonist rotigotine and its use leads to significant improvements in on time and decreased dyskinesia intensities, although this approach has its own limitations, which include local skin reactions and difficulties with adhesion leading to early sloughing off. [17][18][19] Conjugation of pharmaceuticals to stable biodegradable polymers, such as polyethylene glycol and hyaluronic acid, can improve bioavailability of proteins and small molecule drugs. 20 Polyoxazolines (POZs) are one of the bioconjugate polymers that show early promise in drug delivery.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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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 significant 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 determination 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 persisted up to 5 days posttreatment. Repeated weekly dose administration of SER‐214 to normal rats for up to 12 weeks demonstrated highly reproducible pharmacokinetic 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 viable, once‐per‐week therapy for PD patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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“…In addition, the following other anti-Parkinson medications were allowed after 1 month of open-label rotigotine maintenance: monoamine oxidase B inhibitors, anticholinergic agents, N-Methyl-D-aspartate receptor-antagonists (e.g., amantadine), entacapone and modafinil. Complete inclusion and exclusion criteria are published [15][16][17][18][19].…”

Section: Designmentioning

confidence: 99%

“…The benefit of treating patients with early PD with rotigotine has been demonstrated in both short-and long-term studies. Two randomized, placebo-controlled studies of 6-month maintenance (SP512 and SP513) have shown rotigotine transdermal patch to be an efficacious therapy in early-stage PD, producing significant improvements in activities of daily living and motor symptoms, as assessed by UPDRS II + III total score [15][16][17]. The SP702 and SP716 studies were longterm, single-arm, open-label extensions of the SP512 and SP513 studies.…”

Section: Introductionmentioning

confidence: 99%

Impact of 6-month earlier versus postponed initiation of rotigotine on long-term outcome:post hocanalysis of patients with early Parkinson’s disease with mild symptom severity

Timmermann¹,

Asgharnejad²,

Boroojerdi³

et al. 2015

Expert Opinion on Pharmacotherapy

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“…For rotigotine, Watts et al 60 found, with a mean dose of 5.7 mg/24 hours, a decrease in UPDRS subtotal score (part II ADL plus part III Motor) of 5.28 points, compared with placebo. The part III Motor score decreased by 3.5 points.…”

Section: Da Agonists: Phase III Clinical Trial Results Early Pdmentioning

confidence: 99%

Current Status of Symptomatic Medical Therapy in Parkinson’s Disease

Factor

2008

Neurotherapeutics

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Summary: Symptomatic medical therapies for Parkinson's disease (PD) have been disease modifying and have led to improvement in daily function, quality of life, and survival. For 40 years, these therapies have been primarily dopaminergic, and currently include the dopamine (DA) precursor levodopa (LD), DA agonists, catechol-O-methyltransferase (COMT) inhibitors, and monoamine oxidase (MAO) inhibitors. The roles of all these classes of agents have evolved, with significant changes occurring since the early 2000s. This article reviews the current literature for each of these classes of drugs, with a focus on efficacy and place in the therapeutic scheme. Levodopa is no longer considered to be toxic and, thus, its early use is not only appropriate but recommended.Ergot agonists are no longer in use, and new agents administered in patch form or subcutaneous injections have been approved. The COMT inhibitor tolcapone, with its significant efficacy, has been reintroduced, and two new MAO inhibitors have been approved. Selected safety issues are discussed, including the incidence of melanoma in relation to LD; pathological gambling and DA agonists; hepatic toxicity of tolcapone; and the tyramine or so-called cheese reaction with MAO B inhibitors. The article closes with a discussion of future directions and new drugs under development.

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Randomized, blind, controlled trial of transdermal rotigotine in early Parkinson disease

Abstract: Transdermal rotigotine, when titrated to a dosage of 6 mg/24 h, was effective for the treatment of early-stage Parkinson disease in this trial. Adverse events were similar to those found with other transdermal systems and dopamine agonists.

Cited by 234 publications

References 17 publications

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

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

Impact of 6-month earlier versus postponed initiation of rotigotine on long-term outcome:post hocanalysis of patients with early Parkinson’s disease with mild symptom severity

Current Status of Symptomatic Medical Therapy in Parkinson’s Disease

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