A Randomized Thorough QT Study of Apomorphine Sublingual Film in Patients With Parkinson's Disease.

A randomized thorough QT study was conducted to assess the effects of apomorphine sublingual film (SL-APO) on corrected QT interval (QTc) and other cardiac conduction parameters in patients with Parkinson's disease (PD) and "OFF" episodes. Patients were titrated to an SL-APO dose that resulted in FULL "ON," followed by up to two additional doses (maximum 60 mg), then randomized at the highest tolerated dose to a treatment sequence of SL-APO, placebo, and moxifloxacin (400 mg, positive control) in a three-way crossover design. Changes from baseline in time-matched, placebo-adjusted Fridericia-corrected QTc interval (ΔΔQTcF) and Bazett-corrected QTc interval (ΔΔQTcB) were analyzed from postdose electrocardiograms. Forty patients were randomized and received single doses of study treatments. Upper limits of 90% confidence intervals (CIs) for ΔΔQTcF of SL-APO were below the 10-millisecond regulatory threshold at all prespecified timepoints, demonstrating no clinically significant effect on QTcF. Lower limits of 90% CIs for ΔΔQTcF of moxifloxacin exceeded the 5-millisecond regulatory threshold at all timepoints up to 3 hours, confirming assay sensitivity. SL-APO had no clinically meaningful effects on QTcB, PR/QRS intervals, heart rate, or electrocardiogram-derived morphology (EudraCT identifier: 2016-001762-29; ClinicalTrials.gov identifier: NCT03187301).

Dose optimization of apomorphine sublingual film for treating "OFF" episodes in Parkinson's disease.

INTRODUCTION: Apomorphine sublingual film is approved for the "on-demand" treatment of "OFF" episodes in Parkinson's disease (PD). Patients must undergo dose titration to determine their most effective and tolerable dose. We assessed whether higher doses than those that provide an initial "ON" response could yield more effective treatment. METHODS: Patients with PD were assessed in the "OFF" state and the apomorphine sublingual film dose was titrated to a level that provided a tolerable "ON" response. The dose was then increased by up to two dose levels, if tolerated. A comparison in the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III scores was made following administration of the dose that provided the initial "ON" response and following the higher dose. Treatment-emergent adverse events were also reported. RESULTS: Thirty-five patients were titrated to higher apomorphine sublingual film doses than those that provided an initial "ON" response. A mean improvement in MDS-UPDRS Part III score was observed compared with the initial dose of 5.6 points (P = 0.034), 4.4 points (P = 0.009), and 3.7 points (P = 0.018) at 30, 60, and 90 min postdose, respectively. Adverse events were mild or moderate and resolved with dose reduction without concomitant treatment. CONCLUSION: Higher doses of apomorphine sublingual film than those initially perceived to provide an "ON" response can be tolerated and provide additional improvement in motor function in many patients.

Psychogenic movement disorders.

Psychogenic movement disorders (PMDs) represent a challenging dilemma for the treating neurologist. The terminology to classify this disorder is confusing and making the diagnosis is difficult. Once the diagnosis has been established, treatment options are limited, and the patient generally does not accept the diagnosis.

The TOR1A polymorphism rs1182 and the risk of spread in primary blepharospasm.

We studied the influence of the rs1182 polymorphism of the TOR1A gene on the risk of dystonia spread in two representative cohorts of patients presenting with primary blepharospasm (BSP), one from Italy and the other from the United States of America. The relationship between rs1182 polymorphism and spread was estimated by Kaplan-Meier survival curves and Cox proportional hazard regression models adjusted by age and sex, age of BSP onset. In both series, patients carrying the T allele (G/T or T/T) in the rs1182 polymorphism were more likely to have dystonia spread as compared with the homozygous carriers of the common G allele. The comparable findings obtained in two independent cohorts support a genetic contribution to BSP spread.