Subcutaneous Levodopa Infusion for Parkinson's Disease: 1-Year Data from the Open-Label BeyoND Study.

BACKGROUND: Continuous, subcutaneous (SC) levodopa/carbidopa infusion with ND0612 is under development as a treatment for patients with Parkinson's disease (PD) and motor fluctuations. OBJECTIVE: Evaluate 1-year safety data. METHODS: BeyoND is an open-label study evaluating the long-term safety of two ND0612 dosing regimens. RESULTS: Of the 214 enrolled patients (24-hour SC infusion: n = 90; 16-hour SC infusion: n = 124), 120 (56%) completed 12 months of treatment. Leading causes for study discontinuation were consent withdrawal (19.6%) and adverse events (17.3%). Rates of discontinuation were reduced from 49% to 29% after a protocol revision and retraining. Systemic safety was typical for PD patients treated with levodopa/carbidopa. Most patients experienced infusion site reactions, particularly nodules (30.8%) and hematoma (25.2%), which were judged mostly mild to moderate and led to discontinuation in only 10.3% of the participants. CONCLUSIONS: Subcutaneous levodopa/carbidopa continuous infusion with ND0612 is generally safe, with typical infusion site reactions for SC delivery as the main adverse event. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Momentary stress-induced food craving: An ecological momentary assessment study comparing perceived interpersonal and non-interpersonal stressors.

Daily-life stressors and food cravings are dynamic and vary within and across persons. Some evidence suggests interpersonal stressors increase appetite. However, little is known about the association of food craving with different types of stressors at the momentary level in the general population. We aimed to explore the momentary relationships between daily-life stressful events and food craving in a non-clinical community sample, and to compare the associations with food craving when the most stressful event was perceived as interpersonal versus non-interpersonal. We used ecological momentary assessment (EMA) to collect reports on the most stressful event, perceived stressor type, stressor appraisal, and food craving from 123 adults three times a day scheduled at fixed intervals over 10 days. Mixed effects random intercepts and slopes models examined the within- and between-person associations. Experiencing a stressor was significantly positively associated with within-person food craving at the same measurement. No differences in momentary food craving were found when the most stressful event was perceived as interpersonal or non-interpersonal (within-person level). However, frequently reporting the most stressful event as interpersonal (vs. non-interpersonal) was positively associated with food craving across the study (between-person level), particularly when the stressor was appraised as more unpleasant. Daily-life stressors were associated with momentary food craving. Individuals who generally perceived interpersonal stressors as their most stressful event tended to experience food cravings. Future research could further investigate the role of interpersonal stressors as a factor for overeating in daily life and the potential benefits of stress management in interventions.

Trauma history predicts depression and posttraumatic stress symptoms better than a psychiatric diagnosis: Comparing wartime, routine time, and early COVID-19 in Israel.

Individuals with a psychiatric diagnosis and those with a history of trauma are at high risk for depression and posttraumatic stress symptoms (PTSS) following exposure to new traumatic events. Nevertheless, research is scarce on how having both a psychiatric diagnosis and a trauma history affect reactions to new traumatic events, and how different trauma types may affect individuals with a psychiatric diagnosis. We thus examined whether different stressful contexts (War and COVID-19) affected individuals with and without a psychiatric diagnosis differentially and whether results might be explained by prior trauma exposure. In the same cohort, we assessed depression and PTSS during wartime (2014), routine time (2016), and during the COVID-19 pandemic (2020) in a sample with (n = 89) and without (n = 104) a self-reported psychiatric diagnosis. This cohort was recruited during the 2014 Israel-Gaza War using social media, snowballing and outreach to mental health rehabilitation centres. We used a linear mixed modelling approach on data from the entire sample, as well as on the two study groups separately. We found that trauma history predicted PTSS and depression whereas a history of psychiatric diagnosis did not. Regarding trauma types, we found that individuals in the psychiatric diagnosis group relative to themselves had more symptoms during COVID-19 compared to war and routine time, while those without diagnosis had more PTSS and depression symptoms during wartime compared to routine time and COVID-19. In conclusion, a traumatic past may have an important influence on reactions to different types of traumatic events. Distinct traumatic events may affect individuals with or without a psychiatric diagnosis differentially.

The Effects of the Processing of Positive Memories Technique on Posttrauma Affect and Cognitions Among Survivors of Trauma: Protocol for a Daily Diary Study.

BACKGROUND: The Processing of Positive Memories Technique (PPMT) is a promising new treatment approach for posttraumatic stress disorder (PTSD), which involves detailed narration and processing of specific positive autobiographical memories. Indeed, preliminary case-series studies have found reductions in PTSD symptoms, negative affect, and negative cognitions among survivors of trauma who have received PPMT. However, PPMT's effects have not been investigated at the daily level. In this study, we describe the protocol for a study that will examine the daily-level impacts of PPMT in a trauma-exposed, nonclinical community sample. OBJECTIVE: This study uses an innovative research protocol that combines case-series design and daily diary approaches to examine changes in daily affect, daily cognitions, and daily PTSD symptoms pre- and post-PPMT. We hypothesize that at the daily level, in comparison to their own pre-PPMT levels, following the PPMT intervention, participants will report (1) a lower count of endorsed daily PTSD symptoms, (2) increases in daily positive affect and decreases in daily negative affect, (3) increases in positive affect reactivity to daily positive events, and (4) decreases in daily posttrauma cognitions. METHODS: We are currently recruiting participants (target n=70) from a metroplex in the southwest United States. Following a screening survey, eligible participants complete a preintervention baseline survey, followed by 21 daily surveys in their natural environments. Then, they receive 4 PPMT sessions on a weekly basis. After the conclusion of the PPMT intervention, participants complete a postintervention outcome survey and 21 daily surveys. To compare daily affect, daily cognitions, and daily PTSD symptoms before and after PPMT, we will use the daily diary report data and conduct multilevel random intercepts and slopes linear regression models. RESULTS: Data collection was initiated in March 2022 and is expected to end by June 2024. As of November 28, 2023, a total of 515 participants had consented to the study in the screening phase. No analyses will be conducted until data collection has been completed. CONCLUSIONS: Study findings could clarify whether deficits in positive autobiographical memory processes may also characterize PTSD alongside deficits in traumatic memory processes. Furthermore, PPMT could be an additional therapeutic tool for clinicians to help clients reduce posttraumatic distress in their everyday lives. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51838.

P2B001 (Extended Release Pramipexole and Rasagiline): A New Treatment Option in Development for Parkinson's Disease.

Despite levodopa's superior efficacy in reducing the motor symptoms of Parkinson's disease (PD), its risk to induce motor complications requires consideration of the pros and cons of initiating treatment with levodopa-sparing strategies. The current drive toward early levodopa monotherapy is primarily driven by safety and tolerability concerns with dopamine agonists and only mild efficacy of other available approaches. Recently, P2B001, a novel once-daily combination of low-dose, extended-release formulations of pramipexole and rasagiline (0.6 mg and 0.75 mg respectively), has entered clinical development. In this drug evaluation, we review the preclinical and current clinical data for P2B001 and its components. The P2B001 combination has the potential to provide greater efficacy than either pramipexole or rasagiline alone and a better tolerability profile compared to higher dosage dopamine agonist monotherapy, while maintaining the advantage of lower motor complication risk than levodopa.

Parkinson's disease is the fastest growing neurologic disorder across the globe. Once diagnosed, it is now generally agreed that there is no clinical rationale to postpone symptomatic treatment in people who develop Parkinson's-related disability. There are three main treatment options available for use in early Parkinson's disease: levodopa, dopamine agonists and monoamine oxidase type B (MAO-B) inhibitors. Of these, there is a current push toward using levodopa as the main first-line therapy. This is primarily because of the significant safety and tolerability concerns with dopamine agonists and only mild efficacy of MAO-B inhibitors. Recently, P2B001, a novel drug formulation combining once-daily, extended-release, low dosages of the dopamine agonist pramipexole and the MAO-B inhibitor rasagiline (0.6 mg and 0.75 mg respectively), has entered clinical development. In this article, the authors review the preclinical and current clinical data on P2B001 and its components. The P2B001 combination has the potential to provide greater efficacy than either pramipexole or rasagiline alone and a better tolerability profile compared to higher dosage dopamine agonist monotherapy, while maintaining the advantage of lower motor complication risk than levodopa.

Continuous Subcutaneous Levodopa Delivery for Parkinson's Disease: A Randomized Study.

BACKGROUND: ND0612 is a continuous, subcutaneous levodopa/carbidopa delivery system in development for patients with Parkinson's disease (PD) experiencing motor fluctuationsObjective:Evaluate the efficacy and safety of two ND0612 dosing regimens in patients with PD. METHODS: This was a 28-day open-label study (NCT02577523) in PD patients with ≥2.5 hours/day of OFF time despite optimized treatment. Patients were randomized to treatment with either a 24-hour infusion (levodopa/carbidopa dose of 720/90 mg) or a 14-hour 'waking-day' infusion (levodopa/carbidopa dose of 538/68 mg plus a morning oral dose of 150/15 mg). Supplemental oral doses of levodopa were permitted for patients in both groups if required. In-clinic assessments of OFF time (primary endpoint) and ON time with or without dyskinesia were determined by a blinded rater over 8 hours (normalized to 16 hours). RESULTS: A total of 38 patients were randomized and 33 (87%) completed the study. Compared to baseline, OFF time for the overall population was reduced by a least squares (LS) mean[95% CI] of 2.0[- 3.3, - 0.7] hours (p = 0.003). ON time with no/mild dyskinesia (no troublesome dyskinesia) was increased from baseline by a LS mean of 3.3[2.0, 4.6] hours (p < 0.0001), and ON time with moderate/severe dyskinesia was reduced by a LS mean of 1.2[- 1.8, - 0.5] hours (p≤0.001). Reduction in OFF time was larger in the 24-hour group (- 2.8[- 4.6, - 0.9] hours; p = 0.004) than in the 14-hour group (- 1.3[- 3.1, 0.5] hours; p = 0.16). Complete resolution of OFF time was observed in 42% (n = 8) of patients in the 24-hour group. Infusion site reactions were the most common adverse event. CONCLUSION: This study demonstrates the feasibility and safety of continuous subcutaneous delivery of levodopa as a treatment for PD and provides preliminary evidence of efficacy.

Evaluating a community fire as human-made vs. natural disaster moderates the relationship between peritraumatic distress and both PTSD symptoms and posttraumatic growth.

Objective: This study examined whether attributing a cause of a community fire to a human-made vs. natural disaster moderated the association between peritraumatic distress (PD) and posttraumatic stress (PTSD) symptoms, as well as between PD and posttraumatic growth (PTG). Method: Participants lived in Israeli communities affected by wide-scale fires in November 2016. At Time 1 (within one month of the fires), 390 participants completed measures. At Time 2 (four months after the fires), 223 of the original participants completed follow-up-questionnaires. Participants reported their PD symptoms at Time 1, and their beliefs regarding the cause of the fire, PTSD symptoms, and PTG at Time 2. Results: Higher levels of PD at Time 1 were associated with higher levels of both PTSD symptoms and PTG at Time 2. Participants who believed that the fires were more of a human-made than natural disaster had stronger associations between PD and PTSD symptoms, and stronger associations between PD and PTG. Conclusions: Attributions regarding the cause of a disaster may be related to both PTSD symptoms as well as PTG. Balanced and responsible public announcements regarding the causes of traumatic events may reduce the deleterious effects in the aftermath of a traumatic event.

A Network Analysis of Peritraumatic Distress Reactions and Their Relation to Posttraumatic Stress Symptoms in People Exposed to Community Fires.

Objective: Research indicates that people who experience more intense peritraumatic reactions are at higher risk of subsequently developing PTSD. The study used network analysis to: 1) explore the network structure of peritraumatic distress reactions; 2) identify clusters of peritraumatic distress reactions; and 3) assess whether central items in the peritraumatic network have stronger network associations with subsequent posttraumatic stress symptoms (PTS). Method: A convenience sample of adults living in communities affected by large-scale community fires in Israel (November 2016) were recruited. Participants completed the 13-item peritraumatic distress inventory (PDI) within one month of the fires (n = 372), and the PTSD checklist for DSM-5 (PCL-5) four months after the fires (n = 199). Network analyses and exploratory graph analysis were conducted. Results: The PDI items were positively connected to each other in a network structure, which divided into two clusters: emotional reactions; and physical/somatic reactions along with guilt and shame. Loss of emotional control was the most central peritraumatic distress symptom. Highly central peritraumatic distress symptoms were not strongly associated with subsequent PTS; rather, physical reactions were most associated with PTS levels four months after the fires. Conclusions: Future studies should investigate targeting peritraumatic physical reactions as an early secondary prevention strategy for PTSD.

Subcutaneous Administration of Carbidopa Enhances Oral Levodopa Pharmacokinetics: A Series of Studies Conducted in Pigs, Mice, and Healthy Volunteers.

OBJECTIVES: Although commercially available levodopa (LD) formulations include carbidopa (CD) or benserazide for gastrointestinal L-aromatic amino acid decarboxylase inhibition, little is known how manipulating CD delivery affects the pharmacokinetics of LD. Our research systematically evaluated the peripheral and central pharmacokinetics of LD during continuous subcutaneous CD delivery. METHODS: We conducted pharmacokinetic experiments in pigs, mice, and humans to characterize effects of continuous subcutaneous CD delivery co-administered with LD as compared with oral LD/CD administration on LD pharmacokinetics. The porcine and human studies compared peripheral LD pharmacokinetic parameters (area under the curves [AUCs], peak plasma concentrations [Cmax], and plasma elimination half-life [t1/2]) and the mouse studies compared brain LD and dopamine concentrations. RESULTS: In the pig, supplementary subcutaneous CD delivery significantly increased the LD t1/2 and AUC versus LD/CD alone and versus additional oral CD administration. In mice, administration of supplementary subcutaneous CD substantially increased mean plasma concentrations of both LD and CD versus oral LD/CD alone at all time points. These increases were mirrored by increased brain dopamine levels for at least the 7 hours of study. In healthy human subjects, continuous subcutaneous CD administration, 3.33 mg/h x24h, increased the plasma LD t1/2, Cmax, and AUC by 17.4%, 40.5%, and 22.3%, respectively (P < 0.003). CONCLUSIONS: This series of studies demonstrates that small continuous dosing of subcutaneous CD has an unexpected effect on LD pharmacokinetics greater than the extent of decarboxylase inhibition achieved by additional oral CD administration.

ND0701, A Novel Formulation of Apomorphine for Subcutaneous Infusion, in Comparison to a Commercial Apomorphine Formulation: 28-Day Pharmacokinetic Study in Minipigs and a Phase I Study in Healthy Volunteers to Assess the Safety, Tolerability, Pharmacokinetics and Relative Bioavailability.

BACKGROUND: Subcutaneous apomorphine is used for the treatment of Parkinson's disease (PD); however, infusion site reactions are a common adverse event (AE), which can lead to treatment discontinuation. Apomorphine formulations that are more tolerable and convenient for use are needed. OBJECTIVE: Our aim was to compare the toxicity and bioavailability of ND0701, a new concentrated formulation of apomorphine free base, with one of the commercially available apomorphine HCl formulations (APO-go®, Britannia Pharmaceuticals Ltd). METHODS: (1) Preclinical study: 16 minipigs were randomly assigned to placebo, APO-go®, and ND0701 groups, and treated for 28 days. Pharmacokinetic, clinical, and pathological assessments were performed. (2) Phase I study: 18 healthy volunteers participated in an open-label, two-sequence, randomized, three single-dose, partial crossover study to compare the pharmacokinetics, safety, and tolerability of ND0701 with APO-go® (1%). RESULTS: (1) Preclinical study: No systemic toxicity was observed in apomorphine-treated minipigs, but local skin reactions were observed at the infusion sites. These effects were less frequent and less severe and recovery was more rapid for ND0701 compared with APO-go®. (2) Phase I study: Both formulations were safe and well tolerated under the conditions of the study and no severe or serious treatment-emergent AEs were reported. Infusion site nodules were reported more frequently, with higher severity, and recovered slower at APO-go®-treated sites compared with ND0701-treated sites. Bioavailability of apomorphine was comparable between the two formulations. CONCLUSION: Based on these pilot studies, ND0701 appears to be superior to APO-go® in terms of tolerability and safety, while maintaining comparable bioavailability with APO-go®, and shows promise as a future treatment for PD.