Optimizing extended-release carbidopa/levodopa in Parkinson disease: Consensus on conversion from standard therapy.

PURPOSE OF REVIEW: To help clinicians optimize the conversion of a patient's Parkinson disease pharmacotherapy from immediate-release carbidopa/levodopa (IR CD/LD) to an extended-release formulation (ER CD/LD). RECENT FINDINGS: Eleven movement disorders specialists achieved consensus positions on the modification of trial-based conversion guidelines to suit individual patients in clinical practice. SUMMARY: Because the pharmacokinetics of ER CD/LD differ from those of IR CD/LD, modification of dosage and dosing frequency are to be expected. Initial regimens may be based on doubling the patient's preconversion levodopa daily dosage and choosing a division of doses to address the patient's motor complications, e.g., wearing-off (warranting a relatively high ER CD/LD dose, possibly at a lower frequency than for IR CD/LD) or dyskinesia (warranting a relatively low dose, perhaps at an unchanged frequency). Patients should know that the main goal of conversion is a steadier levodopa clinical response, even if dosing frequency is unchanged.

Physicians' experience with RYTARY (carbidopa and levodopa) extended-release capsules in patients who have Parkinson disease.

A discussion between Dr. Dee Silver and Dr. Richard Trosch provides insight and advice for physicians considering a switch from immediate-release carbidopa-levodopa (IR CD-LD) to RYTARY as a treatment for patients with Parkinson disease (PD). The dialogue describes how they identify patients with PD who may and may not be successful switching to RYTARY, how they approach the conversion process and patient compliance, and how they address some side effects that may occur after patients begin taking RYTARY. The clinicians also discuss their experiences with how long it takes to establish a stable regimen as well as provide general advice regarding conversion from treatment with IR CD-LD to RYTARY.

Long-Term Treatment with Extended-Release Carbidopa-Levodopa (IPX066) in Early and Advanced Parkinson's Disease: A 9-Month Open-Label Extension Trial.

BACKGROUND AND OBJECTIVE: IPX066 is a multiparticulate extended-release formulation of carbidopa-levodopa, designed to produce prolonged therapeutic levodopa plasma concentrations. This 9-month open-label extension study assessed its long-term safety and clinical utility in early and advanced Parkinson's disease (PD). METHODS: Participants were enrolled from two phase III IPX066 studies and one open-label phase II study. Early PD patients were titrated to an appropriate dosing regimen while advanced patients started with regimens established in the antecedent studies. Adjustment was allowed throughout the extension. Clinical utility measures included the Unified Parkinson's Disease Rating Scale (UPDRS) and Patient Global Impression (PGI) ratings. RESULTS: Among 268 early PD patients, 53.4 % reported adverse events (AEs) and 1.1 % (three patients) discontinued due to AEs; the most frequent AEs were nausea (5.6 %) and insomnia (5.6 %). Among 349 advanced patients, 60.2 % reported AEs and 3.7 % (13 patients) discontinued due to AEs; the most frequent AEs were dyskinesia (6.9 %) and fall (6.6 %). At month 9 (or early termination), 78.3 % of early patients were taking IPX066 three times daily (median: 720 mg/day) and 87.7 % of advanced patients were taking IPX066 three or four times daily (median: 1450 mg/day). Adjusting for 70 % bioavailability relative to immediate-release (IR) carbidopa-levodopa, the median dosages correspond to ~500 and ~1015 mg/day of IR levodopa in early and advanced PD, respectively. Based on the plasma profiles previously observed in PD patients, the IPX066 regimens in the extension can be estimated to provide a levodopa Cmax (maximum plasma drug concentration) similar to or lower than that provided by IR regimens during the antecedent trials. UPDRS and PGI findings showed sustained treatment effects throughout the extension. CONCLUSION: During 9 months of extended use, IPX066 exhibited a safety/tolerability profile consistent with dopaminergic PD therapy.

Determining the efficacy of rasagiline in reducing bradykinesia among Parkinson's disease patients: a review.

BACKGROUND: Bradykinesia has a significant impact on the lives of Parkinson's disease (PD) patients. Consequently, treating this symptom is of particular concern for patients and clinicians. A number of studies have documented the efficacy of rasagiline in reducing the severity of PD symptoms. OBJECTIVE: To summarize studies that specifically examined the impact of rasagiline on bradykinesia symptoms in PD patients across disease severity. METHODS: The EMBASE database was searched for relevant articles published between 2000 and November 2010. RESULTS: Three studies were identified that explicitly examined the effect of rasagiline on the bradykinesia subscale of the Unified Parkinson's Disease Rating Scale (UPDRS) motor examination. In each, 1 mg/day rasagiline significantly reduced bradykinesia scores in patients. CONCLUSION: As a monotherapy or an adjunctive therapy, rasagiline is an effective drug for reducing the severity of bradykinesia in PD patients.

Tolerability and efficacy of switching from oral selegiline to Zydis selegiline in patients with Parkinson's disease.

Selegiline is a monoamine-B specific inhibitor used to treat Parkinson's disease. A Zydis sublingual preparation has more efficient absorption and less first pass amphetamine metabolites. We conducted an open label oral to Zydis switch study to evaluate tolerability of rapid switch, and relative efficacy, in 48 subjects from 5 sites. Overall patients preferred the Zydis preparation. Per clinician global impressions, fluctuations improved and the "on" UPDRS part II scores improved. Total UPDRS and measures of fatigue and sleep were unchanged. Adverse events were mild. Patients generally preferred the Zydis selegiline preparation but the modest difference is of unclear clinical significance given the open label nature of the trial.

Orally disintegrating selegiline in Parkinson patients with dopamine agonist-related adverse effects.

OBJECTIVE: To determine whether adding orally disintegrating selegiline (ODS) while decreasing dopamine agonist (DA) dosages would reduce DA-related adverse effects (AEs) of excessive daytime sleepiness (EDS), pedal edema, hallucinations, and impulse control disorders (ICDs) without compromising efficacy in Parkinson disease (PD) patients. METHODS: This was a 12-week open-label study of 60 PD patients with motor fluctuations and DA-related AEs of EDS, pedal edema, hallucinations, and ICDs. Orally disintegrating selegiline was initiated at 1.25 mg once daily, and down titration of the DA was started with a goal of a 50% reduction by 1 week. At week 6, ODS was increased to 2.5 mg, and further reductions of the DA were allowed if the AEs were not resolved. RESULTS: The addition of ODS allowed a reduction in the mean daily dose of pramipexole from 2.3 to 0.5 mg and immediate-release ropinirole from 11.2 to 2.9 mg. Most subjects reported a reduction or resolution of DA-related AEs; 94% with EDS (n = 50), 73% with pedal edema (n = 26), 86% with hallucinations (n = 15), and 84% with ICDs (n = 25). Mean activities of daily living and motor scores from the Unified Parkinson's Disease Rating Scale as well as quality-of-life scores were significantly improved without an increase in daily "off" time. The most common AEs, most of which resolved after titration, were worsening of PD, nausea/vomiting, dyskinesia, increased off time, body aches, insomnia, orthostatic hypotension, and increased anxiety and depression. CONCLUSIONS: In most subjects, the addition of ODS with decreasing dosages of DAs substantially reduced EDS, pedal edema, hallucinations, and ICDs without compromising efficacy.

Early, nondisabling Parkinson's disease: weighing the options for initial therapy.

This article on treatment of early idiopathic Parkinson's disease (PD) addresses the therapeutic management of the signs and symptoms of PD. It should be read with the understanding that there is more than one way to initiate and manage the early stages of PD.

Clinical experience with the novel levodopa formulation entacapone + levodopa + carbidopa (Stalevo).

Levodopa is the main pharmacologic treatment for Parkinson's disease. However, the long-term administration of levodopa is associated with the development of motor complications which can seriously compromise patient function. Increasing evidence indicates that such problems are related to abnormal pulsatile stimulation of striatal dopamine receptors and that treatments providing more continuous stimulation reduce the risk of motor complications. It is possible that administering levodopa with a reversible catechol-O-methyl transferase inhibitor at frequent intervals might reduce the risk of these complications. Stalevo (Orion) combines levodopa, the dopa-decarboxylase inhibitor carbidopa and the catechol-O-methyl transferase inhibitor entacapone in a single tablet. This review provides an overview of the initial clinical experience gained with Stalevo during clinical trials, including several case studies.