Glycopyrrolate Improves Disability From Sialorrhea in Parkinson's Disease: A 12-Week Controlled Trial.

OBJECTIVE: The objective of this study was to assess the 12-week efficacy and safety of oral glycopyrrolate for moderate-to-severe sialorrhea in Parkinson's disease (PD). BACKGROUND: Chronic moderate-to-severe sialorrhea has a negative impact on quality of life in PD. There is no robust evidence for oral treatments for sialorrhea longer than 1 week. METHODS: This was a 12-week, double-blinded, placebo-controlled, parallel phase II study in patients with PD and Movement Disorder Society-Unified Parkinson's Disease Rating Scale item 2.2 > 2. The intervention was glycopyrrolate up to 4.5 mg/d; the primary outcome was sialorrhea related-disability (Radboud Oral Motor Inventory for Parkinson's Disease-Saliva). We used an intention-to-treat analysis. A P < 0.05 was deemed significant. RESULTS: We recruited 28 patients (age, 71.1 ± 6.9 years; PD duration, 11.4 ± 7.2 years; Radboud Oral Motor Inventory for Parkinson's Disease-Saliva, 22.4 ± 5.7). Glycopyrrolate was superior to placebo at 12 weeks in the Radboud Oral Motor Inventory for Parkinson's Disease-Saliva (between-group difference, 5.3; 95% confidence interval, 1.0-9.6). Dry mouth was the most common adverse event (glycopyrrolate, n = 6; placebo, n = 2). CONCLUSIONS: The results support the efficacy of glycopyrrolate to treat sialorrhea-related disability up to 12 weeks and contribute to addressing unmet nonmotor care needs in PD. © 2020 International Parkinson and Movement Disorder Society.

Botulinum Toxin Type A for Pain in Advanced Parkinson's Disease.

Background and Objective Pain is a frequent symptom in Parkinson's disease (PD), and the therapeutic alternatives are scarce. The goal of this trial was to measure the effects of botulinum toxin type A (BTXA) in the treatment of limb pain in advanced PD. Methods A randomized double-blind crossover versus placebo study of BTXA for limb pain in advanced Parkinson's disease was conducted. Subjects received individualized BTXA/placebo dosing per pain distribution in limbs. The primary outcome was a measure of change in global pain on a numeric rating scale (NRS) at 4 and 12 weeks postinjection and on a visual analogue scale 12 weeks after treatment. Secondary outcomes included the percentage of responders, physician-rated clinical global impressions, MDS-UPDRS and PDQ-39 scores, and adverse events. Results A total of 12 subjects completed the trial. Treatment with BTXA (average dose=241.66 U) produced a significant reduction in NRS score 4 weeks after the injections (-1.75 points, range from -3 to 7, p=0.033). However, there was no significant difference compared to placebo (p=0.70). Participants with dystonic pain showed a greater reduction in NRS score after 4 weeks when treated with BTXA (2.66 points vs. 0.75 for placebo). There were no significant differences for any of the secondary outcomes or significant adverse events. Conclusions Targeted BTXA injections were safe in patients with limb pain and advanced PD; however, the present study failed to show a significant effect when compared to placebo. Further studies may be focused on evaluating the effect of BTXA particularly in dystonic pain.

A randomized, double-blind, placebo-controlled, crossover trial evaluating the effect of intranasal insulin on cognition and mood in individuals with treatment-resistant major depressive disorder.

BACKGROUND: Cognitive dysfunction in major depressive disorder (MDD) is identified as a primary therapeutic target; no current treatment is approved for the treatment of cognitive dysfunction in MDD. We examined whether intranasal insulin offered a beneficial effect across measures of cognitive function in adults with MDD. METHODS: Thirty-five adults (18-65 years of age: 47.09±9.89) meeting criteria for a major depressive episode as per the Diagnostic and Statistical Manual (DSM)-IV-Treatment Revised were included in this randomized, double blind, placebo-controlled, crossover design study. Subjects were not stratified based on baseline cognitive deficit. Subjects were randomized to 4 weeks of either intranasal insulin 40 International Units (IU) taken four times a day (i.e., morning, afternoon, evening, and before bed) (QID) (n=19) or placebo (n=16). RESULTS: No between group differences were observed in change from baseline on total Montgomery Åsberg Depression Rating Scale (MADRS) score (25.98±2.81), in either of the Positive or Negative subscales of the Positive and Negative Affect Schedule (PANAS), or on a global index of neurocognition. The possibility of practice and/or carry over effect could not be excluded. Methodological refinement (e.g., stratification of subjects based on baseline cognitive deficit) may have augmented assay sensitivity. CONCLUSION: Intranasal insulin did not demonstrate statistically significant improvements on overall mood, aspects of emotional processing, neurocognitive function, or self-reported quality of life patient reported outcomes.

What is a clinically important change in the Unified Dyskinesia Rating Scale in Parkinson's disease?

INTRODUCTION: Dyskinesia remain a significant problem in Parkinson Disease (PD). The translation process of novel drug targets for dyskinesia has proven difficult with several failures at phase III level. Determining the 'clinically important change' (CIC) for dyskinesia rating scales in phase II clinical trials may assist in optimizing drug development of new anti-dyskinetic treatments. We used a standard phase IIa acute levodopa infusion paradigm to determine for the first time the CIC for dyskinesia using the new UDysRS. METHODS: We performed a randomized, double-blind, placebo-controlled crossover study with eleven PD patients with stable bothersome dyskinesia. We used the following patient-reported clinically important events as CIC anchors: onset, maximum intensity, remission of dyskinesia. Objective dyskinesia scores using the UDysRS part III Impairment were determined at these same events by blinded video-rating. The CIC was determined using the 'within-patient' score change and a sensitivity- and specificity-based approach. RESULTS: Patients were most aware of 'onset of dyskinesia', followed by 'remission of dyskinesia'. An 11.1-point median change (UDysRS Part III Impairment, p < 0.0001) was the CIC for patient-reported remission of dyskinesia from a practically defined-OFF state. A 2.32-point change (UDysRS Part III Impairment) had the best specificity and sensitivity to distinguish between patient-reported remission and perception of dyskinesia. CONCLUSIONS: In this study, we provide the first report of a CIC for the UDysRS Part III Impairment. Early knowledge of a CIC may help inform the decision to advance into phase III trials and contribute for a higher yield of success in finding new anti-dyskinetic treatments.

Famotidine, a Histamine H2 Receptor Antagonist, Does Not Reduce Levodopa-Induced Dyskinesia in Parkinson's Disease: A Proof-of-Concept Study.

The neural mechanisms underlying levodopa-induced dyskinesia (LID) in Parkinson's disease (PD) may involve histamine (H2) receptors on striatopallidal pathways. We recently demonstrated that the clinically available oral histamine H2 receptor antagonist (H2 RA), famotidine, can reduce l-dopa-induced chorea in MPTP-lesioned macaques. We hypothesized that famotidine may be useful in the treatment of LID in PD patients. We performed a proof-of-concept, double-blind, randomized, multiple cross-over (4×) trial. Seven PD subjects with bothersome dyskinesia were randomized to oral famotidine 80, 120, and 160 mg/day and placebo. Each subject was randomized to receive each of the four treatment phases for 14 days followed by a 7-day wash-out period between each treatment phase. The primary outcome measure was change in the Unified Dyskinesia Rating Scale (UDysRS; part III) between placebo and famotidine. Secondary outcomes were UDysRS (parts I and II), Global Impression of Change, Lang-Fahn Activities of Daily Living Dyskinesia Scale, Unified Parkinson's Disease Rating part III, and adverse events (AEs). Outcomes were evaluated pre- and post-treatment per dose and analyzed using a mixed-effects linear model. There was no significant effect of famotidine treatment on any of the primary or secondary outcome measures compared to placebo (each dose and all doses combined). There were no significant AEs. Even though the sample size of the current study is limited, famotidine seems to be safe in patients with PD and LID, but showed no potential as an antidyskinetic agent.