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Background: Tablet formulations of Parkinson's disease (PD) medications may become ineffective at managing motor fluctuations in advanced PD. The liquid formulation, levodopa carbidopa ascorbic acid solution, or LCAS, is an effective and inexpensive treatment for motor fluctuations however it remains underutilized. Objective: We compared the efficacy of LCAS with tablet formulations and Duodopa jejunal infusion through routine inpatient management using hourly functional status measures, the Timed Up and Go Test (TUG). The TUG differentiates between 'off' and 'on' states and quantifies motor fluctuations. Methods: Experienced nurses used the TUG times and functional observations recorded hourly throughout the waking day to optimize the LCAS hourly dose and the Duodopa flow rate over several days. When patients were stabilized on each of the interventions, the TUG measures were then recorded to compare the outcomes of the interventions. Results: Twenty-six participants had TUG times recorded while on one or more of the formulations: 19 had TUG times recorded on tablets, 23 on LCAS and 10 on Duodopa. TUG times on LCAS and Duodopa were significantly faster compared to tablets (p < 0.0001, p = 0.001 respectively). Severity of dyskinesia was not significantly different between formulations (p = 0.35). Daily dose for the three formulations and the hourly doses for LCAS and Duodopa did not differ significantly (p = 0.37, p = 0.19 respectively). Conclusion: This report demonstrated the efficacy of LCAS for improving motor complications and its equivalency with Duodopa jejunal infusion. [ABSTRACT FROM AUTHOR]

Introduction: Carbidopa/levodopa enteral suspension (CLES) previously demonstrated reduction in total daily OFF from baseline by over 4 hours in advanced Parkinson’s disease patients across 54 weeks. Evidence on CLES’s long-term effectiveness on patterns of motor-symptom control throughout the day remains limited. Methods: We present post-hoc analyses of a large, open-label study of CLES monotherapy (N = 289). Diary data recorded patients’ motor states at 30-minute intervals over 3 days at baseline and weeks 4, 12, 24, 36, and 54. Adjusted generalized linear mixed models assessed changes from baseline at each timepoint for four outcome measures: time to ON without troublesome dyskinesia (ON-woTD) after waking, motor-symptom control as measured by motor states’ durations throughout the day, number of motor-state transitions, and presence of extreme fluctuations (OFF to ON with TD). Results: Patients demonstrated short-term (wk4) and sustained (wk54) improvement in all outcomes compared to baseline. At weeks 4 and 54, patients were more likely to reach ON-woTD over the course of their day (HR: 1.86 and 2.51, both P

Introduction: A clinical trial in advanced Parkinson's disease (APD) has established the superiority of carbidopa/levodopa enteral suspension (CLES) in reducing total patient "off" time (OFF) and increasing total "on" time without troublesome dyskinesia (ON-woTD) over orally administered immediate-release carbidopa/levodopa tablets (IR–CL). However, temporal patterns of these improvements throughout the waking day have not been examined. In this analysis, time to ON-woTD after waking and patterns of motor-symptom control throughout the waking day were compared between CLES and IR–CL. Methods: Post hoc analyses of APD patient-diary data from the phase 3 randomized controlled trial were used to compare changes in time to ON-woTD after waking, motor-symptom control throughout the waking day, occurrence of extreme fluctuations between OFF and "on" with troublesome dyskinesia, and motor-state transitions with CLES versus IR–CL from baseline to week 12. Results: The sample included 33 CLES-treated and 30 IR–CL-treated patients. Among the CLES group, the percentage of patient days achieving ON-woTD within 30 min of waking was three times higher at week 12 versus baseline (33% vs. 11%, p = 0.0043); no significant change occurred with IR–CL. When the waking day was divided into four 4-h periods, CLES versus IR–CL treatment produced significantly greater reductions in OFF during three periods, and two periods had increased ON-woTD. Fewer CLES-treated patients had extreme fluctuations at week 12 (3% vs. 23%, p = 0.0224) compared to IR–CL-treated patients. From baseline to week 12, CLES-treated patients had greater reductions in the average number of motor-state transitions compared to IR–CL-treated patients (− 1.6, p = 0.0295). Conclusion: CLES-treated patients experienced a more rapid onset of ON-woTD after waking and greater consistency of ON-woTD throughout their waking day than IR–CL-treated patients. Plain Language Summary: In advanced Parkinson's disease, patients' motor-symptom states (such as "on" time without troublesome dyskinesia [good "on" time] and "off" time), and the timing at which they occur, can impact patients' quality of life and ability to complete activities of daily living. Carbidopa/levodopa enteral suspension is administered continuously into the jejunum, potentially reducing some of the motor-state variation that is common with orally administered carbidopa/levodopa, including delayed "on" time after waking and transitions between "off" and "on" throughout the day. In post hoc analyses of clinical trial data, patterns of motor-states across the waking day were compared between carbidopa/levodopa enteral suspension and orally administered immediate-release carbidopa/levodopa at week 12. Outcomes included time to good "on" after waking; occurrence of extreme fluctuations between "off" time and "on" time with troublesome dyskinesia; time in each motor-state during 4-h intervals across the day; and frequency of motor-state transitions. Three times as many carbidopa/levodopa enteral suspension-treated patients achieved good "on" within 30 min of waking after 12 weeks versus baseline, whereas no significant change was observed for the orally administered immediate-release carbidopa/levodopa group. Compared to orally administered immediate-release carbidopa/levodopa-treated patients, fewer carbidopa/levodopa enteral suspension-treated patients experienced extreme fluctuations, had greater reductions in motor-state transitions, and greater reductions in duration of "off" during three of the four intervals in the day. These findings provide a first look at the impact of carbidopa/levodopa enteral suspension on motor-state patterns throughout the day, and suggest that carbidopa/levodopa enteral suspension provides more consistent motor-symptom control and predictable benefit throughout the day than orally administered carbidopa/levodopa. [ABSTRACT FROM AUTHOR]

Advanced Parkinson's disease is inconsistently defined, and evidence is lacking in relation to device-aided therapies. To update existing reviews of intrajejunal infusion of levodopa/carbidopa (LCIG), we performed a literature search for relevant articles (to November 3, 2020) using PubMed supplemented by hand searching. Retrieved articles were categorized by relevance to identified research questions, including motor complications and symptoms; nonmotor symptoms; functioning, quality of life, and caregiver burden; optimal timing of treatment initiation and administration duration; discontinuation; and complications. Most eligible studies (n = 56) were open-label, observational studies including relatively small patient numbers. LCIG consistently reduces OFF time and increased ON time without troublesome dyskinesia with varying effects regarding ON time with troublesome dyskinesia and the possibility of diphasic dyskinesia. More recent evidence provides some increased support for the benefits of LCIG in relation to nonmotor symptoms, quality of life, activities of daily living, and reduced caregiver burden. Patient age does not appear to significantly impact the effectiveness of LCIG. Discontinuation rates with LCIG (~17%-26%) commonly relate to device-related issues, although the ability to easily discontinue LCIG may represent a potential benefit. LCIG may be a favorable option for patients with advanced Parkinson's disease who show predominant nonmotor symptoms and vulnerability to complications of other advanced therapy modalities. Larger, well-controlled studies, including precise investigation of cost effectiveness, would further assist treatment selection. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background and purpose: Recent data suggest that imbalances in the composition of the gut microbiota (GM) could exacerbate the progression of Parkinson disease (PD). The effects of levodopa (LD) have been poorly assessed, and those of LD‐carbidopa intestinal gel (LCIG) have not been evaluated so far. The aim of this study was to identify the effect of LD and LCIG, in particular, on the GM and metabolome. Methods: Fecal DNA samples from 107 patients with a clinical diagnosis of PD were analyzed by next‐generation sequencing of the V3 and V4 regions of the 16S rRNA gene. PD patients were classified in different groups: patients on LCIG (LCIG group, n = 38) and on LD (LD group, n = 46). We also included a group of patients (n = 23) without antiparkinsonian medicaments (Naïve group). Fecal metabolic extracts were evaluated by gas chromatography mass spectrometry. Results: The multivariate analysis showed a significantly higher abundance in the LCIG group of Enterobacteriaceae, Escherichia, and Serratia compared to the LD group. Compared to the Naïve group, the univariate analysis showed a reduction of Blautia and Lachnospirae in the LD group. Moreover, an increase of Proteobacteria, Enterobacteriaceae, and a reduction of Firmicutes, Lachnospiraceae, and Blautia was found in the LCIG group. No significant difference was found in the multivariate analysis of these comparisons. The LD group and LCIG group were associated with a metabolic profile linked to gut inflammation. Conclusions: Our results suggest that LD, and mostly LCIG, might significantly influence the microbiota composition and host/bacteria metabolism, acting as stressors in precipitating a specific inflammatory intestinal microenvironment, potentially related to the PD state and progression. [ABSTRACT FROM AUTHOR]

Background/aim: Levodopa-carbidopa intestinal gel (LCIG) is an effective treatment modality in the management of advanced Parkinson's disease (PD) despite frequent adverse events and different rates of dropouts. Efficacy and safety data regarding Turkish patients on LCIG are limited. This study aims to report in detail the efficacy and adverse effect profile of LCIG among advanced PD patients from a Turkish center for movement disorders. Materials and methods: Twenty-two patients (50% male) who started receiving LCIG between December 2014 and March 2020 were recruited. The efficacy of LCIG was assessed with the Unified Parkinson's Disease Rating Scale (UPDRS III), Clinical Global İmprovement (CGI) scale, and Quality of Life scale (PDQ8). Improvements in gait disorders and nonmotor features were also questioned. Adverse events (AE) were collated into 3 topics: related to percutaneous endoscopic gastrojejunostomy (PEG-J), device-related, and LCIG infusion-related. Results: Mean age and pre-LCIG disease duration were 66.7 (8.8) and 13.3 (8.0) years respectively. UPDRS III scores and H-Y scale assessments significantly improved. Better quality of life scores, clinical global improvements, and improvements in dysarthria, dysphagia, and gait were observed. None of our patients dropped out or died during a mean 17.5-month (12.3) period. Overall 20 (90.9%) patients experienced at least one AE. Twelve patients had PEG-J--related complications; three had acute abdomen. Eight (36.4%) patients had device-associated problems. Half of the patients required at least one additional endoscopic procedure and 7 had a device replaced. Mean body weight decreased from 69.5 to 62.5 kg and seven patients had newly onset PNP at a follow-up electromyography. Dyskinesia related to LCIG infusion was observed in 5 (22.7%) patients. There was no significant increase in hallucination among patients. Conclusion: LCIG is an efficient treatment modality in the management of Turkish patients with advanced Parkinson's disease. Although most of the patients had at least one AE, none of them dropped out. Patient selection, patient compliance, and collaborative management are important steps affecting the success of modality. [ABSTRACT FROM AUTHOR]

Background: Continuous intra-duodenal infusion of levodopa-carbidopa intestinal gel (LCIG) is a well-established therapy for patients with advanced Parkinson's disease (PD) suffering from motor complications despite optimized treatment with oral dopaminomimetics. However, time to discontinuation of treatment with LCIG varies considerably between patients, ranging from a few months to more than ten years. To improve the selection of candidates for LCIG, knowledge of prognostic factors is of paramount importance. Objective: To explore baseline predictors of time to discontinuation of LCIG. Methods: In this two-center retrospective cohort study, we reviewed the medical files of 98 PD patients treated with LCIG between April 2006 and December 2015 (53% male; mean age: 66.2 years; mean disease duration: 12.3 years). Baseline patient characteristics were used as covariates in Cox regression models. Results: During follow-up (mean observation time: 2.6 years; range: 0.1–9.3) eighteen patients discontinued treatment (18.4%), while seven patients died (7.1%). Median duration of treatment with LCIG, estimated with Kaplan-Meier analysis, was 7.8 years (95% CI: 6.7–9.0). Disease duration (in years) at baseline was a statistically significant predictor of time to discontinuation of LCIG (HR: 0.85; 95% CI: 0.75–0.96, p = 0.006). All other characteristics studied, e.g. age >70 years, did not show statistically significant associations with the total duration of treatment with LCIG. Conclusion: Our findings show a low overall rate of discontinuation of LCIG infusion, with a median duration of treatment of 7.8 years. Shorter disease duration at baseline appeared to be a predictor of earlier discontinuation of LCIG. [ABSTRACT FROM AUTHOR]

The aim of the study was to point out the contribution of new invasive therapeutic procedures in the treatment of advanced stages of Parkinson's disease (PD) in comparison with classical oral pharmacotherapy. Data originated from a group of 43 patients with PD, 39% (17) with classic treatment, 23% (10) with intestinal gel of methyl ester levodopa (Duodopa), 19% (8) of patients were using subcutaneous delivery of apomorphine (APO) and the same quantity of patients had undergone deep brain stimulation (DBS). Majority of patients had advanced stages of PD, stage 4, by standards of Hoehn and Yahr scale (Hoehn and Yahr, 1967). Research observed improvement in majority of patients with novel treatments. A positive effect was also noted in the reduced need for oral therapy, where there was a significant decrease in all new therapies. Benefits were observed in the amount of antiparkinsonic drugs taken per os, where we observed reduction in all new therapies. A positive effect of the new therapeutic approaches in reducing "off" periods in patients has also been noted. In the case of Duodopa and DBS, the "off" period was shortened up to 50% and in the apomorphine pump up to 40%. Patients also reported reduction of some symptoms like rigidity, tremor and bradykinesis while dyskinesis still remains suba challenge. On the basis of the obtained results, it can be concluded that new therapeutic procedures for PCh will make it possible to manage symptoms typical of advanced stages of the disease, which without these procedures would lead to disability, which is the main reason for their indication. However, in early stages, well responding patients or in slow progressing disease oral antiparkinsonics are remaining as golden standard of treatment. This is not just due to good response but also because these classic drug formulations are significantly less expensive. In Slovakia, novel treatments are accessible through healthcare insurance only after secondary revision by insurance company doctors.

In 2015, the US Food and Drug Administration approved levodopa-carbidopa intestinal gel (LCIG; also known as carbidopa-levodopa enteral suspension in the US) for the treatment of motor fluctuations in patients with advanced Parkinson's disease. LCIG provides a continuous infusion of levodopa and carbidopa by means of a portable pump and percutaneous endoscopic gastrojejunostomy tube. The delivery system has a two-fold pharmacokinetic advantage over orally administered carbidopa/levodopa. First, levodopa is delivered in a continuous rather than intermittent, pulsatile fashion. Second, delivery to levodopa's site of absorption in the jejunum bypasses the stomach, thereby avoiding issues with erratic gastric emptying. In blinded prospective clinical trials and observational studies, LCIG has been shown to significantly decrease "off" time, increase "on" time without troublesome dyskinesia, and reduce dyskinesia. Consistent with procedures in previous studies, LCIG initiation and titration in the pivotal US clinical trial were performed in the inpatient setting and followed a standardized protocol. In clinical practice, however, initiation and titration of LCIG have a great degree of flexibility and, in the US, almost always take place in the outpatient setting. Nonetheless, there remains a significant amount of clinician uncertainty regarding titration in outpatient clinical practice. This review aims to shed light on and provide guidance as to the current methods of titration in the outpatient setting, as informed by the medical literature and the authors' experiences. FUNDING: AbbVie, Inc. Plain language summary available for this article. [ABSTRACT FROM AUTHOR]

Development of motor fluctuations and dyskinesia characterizes the transition from early to advanced Parkinson disease stage. Current therapeutic strategies to manage motor complications aim at increasing the number of levodopa administrations and extending its benefit by the association of enzyme blockers and dopamine agonists. However, as disease progresses, mobility becomes progressively dependent on levodopa absorption and its plasma bioavailability, resulting in loss of independence, worse quality of life and increased caregiver burden. If patients continue to experience off-time with functional impact on activities of daily living after best medication adjustments, implementation of infusion with apomorphine or levodopa, and surgical therapies should be considered. Presence of troublesome dyskinesia would also favor the choice of an advanced treatment. Compared with pulsatile oral therapy, both apomorphine and levodopa infusion determine more continuous striatal dopamine receptors stimulation than oral levodopa resulting in significant reduction of off-time and dyskinesia, particularly peak-dose, although not in their complete resolution. This observation proves that abnormal synaptic plasticity and connectivity changes cannot be reversed once they are established. Early implementation of these therapeutic strategies ideally would target patients as soon as motor complications begin rather than at late stage of advanced Parkinson’s disease (PD) before dyskinesia have manifested. Preliminary evidence from early deep brain stimulation in patients with short disease duration and modest motor complications suggests that this approach can positively impact quality of life. It is conceivable that changing our PD treatment algorithm and implementing device-aided therapies at the beginning of the advanced phase before dyskinesia has established, will provide more stable motor conditions and longer functional autonomy. [ABSTRACT FROM AUTHOR]

Background: Levodopa-carbidopa intestinal gel (LCIG; Duodopa®) is used for continuous infusion in advanced Parkinson's disease. To achieve optimal effect, the LCIG dose is individually titrated, traditionally conducted during hospitalization in Sweden. However, dose adjustment depends on surrounding conditions, physical activity, and emotional stress, which is why titration at home could be beneficial. Telemedicine (TM) using a video communication system offers alternative titration procedures, allowing LCIG initiation at home. Objective: Study objectives were to show the feasibility of TM for LCIG home titration, evaluate resource use, and assess patient, neurologist, and nurse satisfaction. Methods: Four clinics enrolled 15 patients to observe efficiency and feasibility of TM-based monitoring. Results: Patient median (range) age was 67 (52-73) years and time since diagnosis was 10 (7-23) years. Median time between LCIG initiation and end of TM-assisted titration was 2.8 (2.0-13.8) days. Median time required for home titration by neurologists, nurses, and patients was (hours:minutes) 1:14 (0:29-1:52), 5:49 (2:46-10:3), and 8:53 (4:11-14:11), respectively. Neurologists and nurses considered this to be less time than required for hospital titration. TM allowed patients 92% free time from start to end of titration. Technical problems associated with TM contacts were rare, mostly related to digital link, and quickly resolved. Patients, neurologists, and nurses were satisfied using TM. No serious adverse events were reported; there was one device complaint (tube occlusion). Conclusions: In this study, TM-assisted LCIG titration at home was resource-efficient, technically feasible, well-accepted and was deemed satisfactory by patients, neurologists, and nurses. [ABSTRACT FROM AUTHOR]

The use of Duodopa ® Levodopa-Carbidopa intestinal gel offers patients with advanced Parkinson's disease (PD) an effective alternative therapy for the treatment of severe motor fluctuations and dyskinesia. This therapy requires the use of percutaneous endoscopic gastrostomy/jejunostomy tube (PEG/J) to deliver gel directly into the jejunum which poses new challenges for neuroscience nurses for the care and management of patients with PD. Due to the reported number of complications associated with PEG/J our facility opted to use a direct jejunostomy tube for the first of two PD patients which resulted in an adverse outcome for our 80 year old patient. This experience highlighted that the neuroscience nurses need to increase knowledge and understanding of PEG/J and jejunostomy care as more future patients will be treated with Duodopa, and that future studies regarding the safety and value of the direct jejunostomy tubes are warranted. [ABSTRACT FROM AUTHOR]

Background Continuous levodopa-carbidopa intestinal gel ( LCIG) diminishes daily 'off' time and dyskinesia in patients with advanced Parkinson′s disease ( PD). Complications are common with percutaneous endoscopic gastrostomy with a jejunal extension tube ( PEG-J). Aim of the Study To report the clinical outcome of LCIG in patients with advanced PD in the years 2006-2014 at Helsinki University Hospital. Patients and Methods Levodopa-carbidopa intestinal gel treatment started following PEG-J placement in patients with advanced PD after successful in-hospital LCIG trial with a nasojejunal tube. Demographics, PEG-J procedures, discontinuation of LCIG, complications and mortality were retrospectively analyzed. Results [mean (SD)] Sixty patients with advanced PD [age 68(7) years; duration of PD: 11(4) years] had LCIG treatment for 26(23) months. The majority of patients with advanced PD were satisfied with the LCIG treatment. For 51 patients (85%), the pump was on for 16 hr a day, and for nine patients (15%) it was on for 24 hr a day. After 6 months, the levodopa-equivalent daily dose ( LEDD) had increased by 30% compared to pre- LCIG LEDD. Sixty patients underwent a total of 156 PEG-J procedures, and 48 patients (80%) had a total of 143 complications. Forty-six patients (77%) had 119 PEG-J or peristomal complications, and 22 patients (37%) had a total of 25 other complications. The most common complications were accidental removal of the J-tube in 23 patients (38%) and ≥5% weight loss in 18 patients (30%). Fifteen patients discontinued the LCIG after 21 (21) months. At the end of the follow-up period of 33(27) months, 38 patients were still on LCIG and nine (15%) had died. Conclusion Most patients were satisfied with LCIG treatment. A few patients lost weight whereas the majority had complications with PEG-J. When LCIG treatment is carried out, neurological and endoscopic units must be prepared for multiple endoscopic procedures. [ABSTRACT FROM AUTHOR]

Background: Levodopa/carbidopa intestinal gel therapy (LCIG) can efficiently improve several motor and non-motor symptoms of advanced Parkinson's disease (PD). The recently developed Movement Disorder Society-sponsored Unified Parkinson's Disease Rating Scale (MDS-UPDRS) improved the original UPDRS making it a more robust tool to evaluate therapeutic changes. However, previous studies have not used the MDS-UPDRS and the Unified Dyskinesia Rating Scale (UDysRS) to assess the efficacy of LCIG.Objectives: Our aim was to determine if the MDS-UPDRS and UDysRS could detect improvement in the experiences of daily living following 1-year LCIG treatment.Methods: In this prospective, multicenter, open-label study, 34 consecutive patients undergoing LCIG treatment were enrolled. Patients were examined twice: prior to LCIG initiation and 12 months later. Impact of PD-related symptoms and dyskinesia was assessed by the MDS-UPDRS and UDysRS.Results: Non-motor Experiences of Daily Living part of MDS-UPDRS improved from 20 (median, interquartile-range, IQR:14-23) to 16 points (median, IQR:12-20, p = 0.044) and the Motor Experiences of Daily Living ameliorated from 24 (median, IQR:20-29) to 18 points (median, IQR:13-25, p = 0.025). Health-related quality of life, measured by PDQ-39, also improved from 35.4 (median, IQR:26.9-50.3) to 27.0 (median, IQR:21.3-31.4) points (p = 0.003). The total score of UDysRS decreased from 47 (median, IQR:36-54) to 34 (median, IQR:21-45) points (p = 0.003).Conclusions: As far as the authors are aware of, our paper is the first to evaluate the impact of LCIG on dyskinesia by the means of UDysRS. Changes in MDS-UPDRS and UDysRS confirm that LCIG treatment can efficiently improve experiences of daily living in advanced PD. [ABSTRACT FROM AUTHOR]

The duration of action of oral levodopa becomes shorter as Parkinson’s disease (PD) progresses. Patients with advanced PD may develop potentially disabling motor fluctuations and abnormal involuntary movement (dyskinesia), which cannot be managed with optimized oral or transdermal PD medications. The progressively worsening symptoms can have a substantial impact on the patient quality of life (QoL). Levodopa–carbidopa intestinal gel (LCIG) is delivered continuously via a percutaneous endoscopic gastrostomy with a jejunal extension (PEG-J). LCIG is licensed for the treatment of levodopa-responsive advanced PD in individuals experiencing severe motor fluctuations and dyskinesia when available combinations of antiparkinsonian medications have not given satisfactory results. Initial evidence for the efficacy and tolerability of LCIG came from a number of small-scale studies, but recently, three prospective studies have provided higher quality evidence. A 12-week double-blind comparison of LCIG with standard levodopa therapy, a 52-week open-label study extension of the double-blind study, and a 54-week open-label safety study, demonstrated significant improvements in ‘off’ time and ‘on’ time without troublesome dyskinesia, and QoL measures that were maintained in the longer term. There are also observations that LCIG may be effective treatment for nonmotor symptoms (NMS) although the evidence is limited. There is a need for further research on the efficacy of LCIG in reducing NMS, dyskinesia and improving QoL. This review surveys the clinical evidence for the effectiveness and tolerability of LCIG in the management of advanced PD and highlights some practical considerations to help optimize treatment. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to investigate in vivo the ability of levodopa/carbidopa intestinal gel infusions to produce sustained striatal dopamine levels and to improve clinical outcomes in Parkinson's disease patients.Methods: Six advanced Parkinson's disease patients had serial [11 C]raclopride PET to assess levodopa/carbidopa intestinal gel infusion-induced rises in striatal dopamine as reflected by a fall in dopamine-D2/3 receptor availability. Parkinson's disease patients had baseline scan OFF-dopaminergic stimulation and 2 scans following initiation of levodopa/carbidopa intestinal gel infusions. Striatal D2/3 binding was measured in striatal subregions corresponding to sensorimotor, limbic, and cognitive/associative function.Results: Mean striatal [11 C]raclopride nondisplaceable binding potential decreased by 14.0% to 16.7% in sensorimotor, 12.0%-14.4% in limbic, and 8.7%-11.6% in cognitive/associative function subregions at 1- to 10-hour points (P < 0.01). Sensorimotor subregion [11 C]raclopride nondisplaceable binding potential reductions correlated with reductions in Unified Parkinson's Disease Rating Scale Part III scores over the course of the infusion (r = 0.81; P < 0.05).Conclusions: Levodopa/carbidopa intestinal gel infusions generate a stable rise in striatal dopamine levels and are associated with improvements in motor manifestations. © 2016 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Continuous infusion of levodopa or apomorphine provide constant dopaminergic stimulations are good alternatives to deep brain stimulation to control motor fluctuations in patients with advanced Parkinson’s disease (PD). Apomorphine provides motor benefit similar to dopamine, but its long-term use is limited by compliance, mostly injection site skin reactions. Administration of levodopa/carbidopa by continuous duodenal infusion allows replacement of all oral medications and permits achievement of a satisfactory therapeutic response paralleled by a reduction in motor complication severity. However, this procedure is more invasive than apomorphine as it requires a percutaneous endoscopic gastrostomy Clinical experience with infusions shows that continuous dopaminergic stimulation of dopaminergic medications reduces dyskinesia and widens the therapeutic window in advanced PD.

Background: Levodopa therapy in Parkinson's disease (PD) is often associated with disabling motor and non-motor complications in patients with advanced disease due to the variable absorption of levodopa because of an irregular or erratic emptying of the gastric content. Methods: Prospective single movement disorder center study using pre-set selection criteria, unified PD scale (UPDRS III), non-motor symptoms scale (NMSS), and PD questionnaire-8 (PDQ-8) to evaluate the efficacy, safety, and long-term treatment outcomes using levodopa-carbidopa intestinal gel (LCIG) infusion in patients with advanced PD, who were followed up every 6 months. Results: Twenty patients were recruited over a period of 6 years. Disease duration prior to LCIG infusion ranged from 5 to 18 years (mean 11.4 ± 4.2). The mean follow-up time on LCIG therapy was 48.5 ± 23.2 months (range 11-83 months). Mean 'off' time, UPDRS III, NMSS, and PDQ-8 improvement were statistically significant. Two patients dropped out and 66.7% of patients required tube replacement. Conclusion: LCIG infusion monotherapy demonstrated significant improvement in reducing the 'off' time, reducing levodopa-induced dyskinesia, and improving non-motor symptoms and quality of life. This therapy is recommended for patients in whom motor fluctuations are inadequately treated with traditional oral PD therapy. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Introduction: Carbidopa/levodopa enteral suspension (CLES) previously demonstrated reduction in total daily OFF from baseline by over 4 hours in advanced Parkinson's disease patients across 54 weeks. Evidence on CLES's long-term effectiveness on patterns of motor-symptom control throughout the day remains limited., Methods: We present post-hoc analyses of a large, open-label study of CLES monotherapy (N = 289). Diary data recorded patients' motor states at 30-minute intervals over 3 days at baseline and weeks 4, 12, 24, 36, and 54. Adjusted generalized linear mixed models assessed changes from baseline at each timepoint for four outcome measures: time to ON without troublesome dyskinesia (ON-woTD) after waking, motor-symptom control as measured by motor states' durations throughout the day, number of motor-state transitions, and presence of extreme fluctuations (OFF to ON with TD)., Results: Patients demonstrated short-term (wk4) and sustained (wk54) improvement in all outcomes compared to baseline. At weeks 4 and 54, patients were more likely to reach ON-woTD over the course of their day (HR: 1.86 and 2.51, both P < 0.0001). Across 4-hour intervals throughout the day, patients also experienced increases in ON-woTD (wk4: 58-65 min; wk54: 60-78 min; all P < 0.0001) and reductions in OFF (wk4: 50-61 min; wk54: 56-68 min; all P < 0.0001). At weeks 4 and 54, patients' motor-state transitions were reduced by about half (IRR: 0.53 and 0.49, both P < 0.0001), and fewer patients experienced extreme fluctuations (OR: 0.22 and 0.15, both P < 0.0001)., Conclusion: CLES monotherapy was associated with significant long-term reductions in motor-state fluctuations, faster time to ON-woTD upon awakening, and increased symptom control throughout the day., Competing Interests: The authors declare the following relationships, which may be considered as potential competing interests: Rajesh Pahwa has received consulting fees from AbbVie, Acadia, Acorda, Adamas, Cynapses, Global Kinetics, Lundbeck, Neurocrine, Pfizer, Sage, Sunovion, Teva Neuroscience, and US World Meds. He has received research grants from AbbVie, Adamas, Avid, Biotie, Boston Scientific, Civitas, Cynapses, Kyowa, National Parkinson Foundation, NIH/NINDS, and Parkinson Study Group. Jason Aldred has been a consultant and received honorarium from AbbVie, Acorda, Adamas, Allergan, Boston Scientific, Teva, Medtronic, and US World Meds. He has also received research support from NINDS, Abbott, AbbVie, Acadia, Biogen, Boston Scientific, Denali, Impax/Amneal, Sunovion, Neuroderm, Novartis, and Theravance. Aristide Merola has received support from the NIH (KL2 TR001426) and speaker or consultancy honoraria from CSL Behring, AbbVie, Abbott, and Cynapsus Therapeutics. He has received grant support from Lundbeck and AbbVie. Prasanna L. Kandukuri, Yanjun Bao, Omar Ladhani, and Connie H. Yan are employees of AbbVie and may own stocks/shares in the company. Niodita R. Gupta is a former employee of AbbVie, currently employed by Johnson and Johnson, and may hold AbbVie stock. Vivek S. Chaudhari is a former employee of AbbVie, currently employed by EMD Serono, Inc. and may hold AbbVie stock. Emi Terasawa, Viviana Garcia-Horton, and David R. Steffen are employees of Analysis Group, Inc., which has received consultancy fees from AbbVie. Stuart H. Isaacson has received honoraria for CME, consultant, research grants, and/or promotional speaker on behalf of: AbbVie, Acadia, Acorda, Adamas, Addex, Allergan, Amarantus, Axovant, Benevolent, Biogen, Britannia, Cerecor, Eli Lilly, Enterin, GE Healthcare, Global Kinetics, Impax, Intec Pharma, Ipsen, Jazz, Kyowa, Lundbeck, Michael J. Fox Foundation, Neurocrine, Neuroderm, Parkinson’s Study Group, Pharma2B, Roche, Sanofi, Sunovion, Teva, Theravance, UCB, US World Meds, and Zambon., (© 2022 The Author(s).)

Aims Levodopa-carbidopa intestinal gel ( LCIG) provides continuous levodopa-carbidopa delivery through intrajejunal infusion. This study characterized the population pharmacokinetics of levodopa following a 16 h jejunal infusion of LCIG or frequent oral administration of levodopa-carbidopa tablets ( LC-oral) in subjects with advanced Parkinson's disease ( PD). Methods A non-linear mixed-effects model of levodopa pharmacokinetics was developed using serial plasma concentrations from an LCIG phase 1 study and a phase 3 double-blind, double-dummy study of the efficacy and safety of LCIG compared with LC-oral in advanced PD patients ( n = 68 for model development; 45 on LCIG and 23 on LC-oral). The final model was internally evaluated using stochastic simulations and bootstrap and externally evaluated using sparse pharmacokinetic data from 311 subjects treated in a long term safety study of LCIG. Results The final model was a two compartment model with a transit compartment for absorption, first order elimination, bioavailability for LCIG (97%; confidence interval = 95% to 98%) relative to LC-oral, different first order transit absorption rate constants ( LCIG = 9.2 h-1 vs. LC-oral = 2.4 h-1; corresponding mean absorption time of 7 min for LCIG vs. 25 min for LC-oral) and different residual (intra-subject) variability for LCIG (15% proportional error, 0.3 μg ml−1 additive error) vs. LC-oral (29% proportional error, 0.59 μg ml−1 additive error). Estimated oral clearance and steady-state volume of distribution for levodopa were 24.8 l h−1 and 131 l, respectively. Conclusions LCIG administration results in faster absorption, comparable levodopa bioavailability and significantly reduced intra-subject variability in levodopa concentrations relative to LC-oral administration. [ABSTRACT FROM AUTHOR]

Data concerning efficacy, safety, and patient satisfaction of levodopa/carbidopa intestinal gel (LCIG, Duodopa, AbbVie, Wavre, Belgium) infusion in routine clinical practice were needed to maintain reimbursement of the drug in Belgium. Patients with advanced Parkinson's disease in 27 neurology centers across Belgium were included. Of 100 patients who underwent naso-intestinal (NI) evaluation with LCIG, 67 received permanent treatment with LCIG via percutaneous endoscopic gastrostomy and jejunal tube (PEG/J). Efficacy was evaluated at baseline (on levodopa) and during a follow-up (FU) visit (on LCIG) using the Unified Parkinson's Disease Rating Scale (UPDRS) IV. Patient appraisal of the Duodopa system was evaluated using a visual analog scale for therapy compliance, user-friendliness, and global appreciation. Safety was assessed by reporting suspected adverse drug reactions (ADRs) and medical device-related complaints. FU evaluations were conducted in 37 patients. Significant improvement at FU was observed for motor complications (UPDRS IV) as the mean change from baseline to FU was −6.3 (95 % CI −8.1 to −4.5). Patient appraisal showed high scores for hospital delivery, user-friendliness, and patient global appreciation, as well as family appreciation of the system on daily life. Few ADRs and system malfunctions were reported, with no unexpected ADRs. In conclusion, the symptoms and impact of Parkinsonism improved markedly when LCIG PEG/J was initiated. [ABSTRACT FROM AUTHOR]

Many studies confirmed the efficacy and safety of continuous infusion of intrajejunal levodopa/carbidopa gel (CIILG) for advanced Parkinson's disease (PD). Although this treatment is widely used, definite inclusion/exclusion criteria do not exist. In this prospective open-label study, we evaluated the long-term outcome in 28 consecutive patients and sought to detect any predictive factor to identify the best candidates for CIILG therapy. The assessment was carried out routinely at baseline, after 6 months and every year with UPDRS III-IV, FOG Questionnaire, non-motor symptoms scale, PD questionnaire (PDQ-8), cognitive and psychiatric status evaluation (MMSE, FAB, NPI) and caregiver's quality of life. 17/28 patients reached the 24-month follow-up. A statistically significant beneficial effect was shown on motor complications in short- and long-term follow-up, also on axial symptoms like gait disturbances. A concomitant improvement in PDQ8 score was observed, with a parallel mild amelioration, but not significant, on Caregivers QoL. When classified according to their outcome on QoL, the only predictive positive factor was less severe at Neuropsychiatric Inventory (NPI) score at baseline. Considering the improvement in motor scores (duration of 'off' period), the more advanced age was associated with a poorer outcome. Our results confirmed a sustained efficacy and safety in long-term follow-up and suggest that younger age at operation and absence or mild presence of psychiatric/behavioural symptoms could be considered valid predicting factors in selecting the best candidates for this efficacious therapy. [ABSTRACT FROM AUTHOR]

Background and purpose Levodopa/carbidopa intestinal gel ( LCIG) infusion is nowadays becoming an established therapeutic option for advanced Parkinson's disease ( PD) patients with fluctuating symptoms unresponsive to conventional oral treatment. As the implementation of LCIG therapy is increasing, there is a need for safety and efficacy data from current clinical practice. Methods All PD patients treated with LCIG at our centre over a 7-year period were analysed to determine the duration of treatment, retention rate, reasons for discontinuation, LCIG efficacy in motor complications, modifications of concomitant therapy and adverse events. Results Of the 59 patients, seven subjects (12%) died of causes unrelated to LCIG infusion and 11 patients (19%) discontinued therapy prior to the cut-off date. Duodopa improved motor complications and over 90% of patients reported an improvement in their quality of life, autonomy and clinical global status. The most common adverse events were dislocation and kinking of the intestinal tube. Conclusions LCIG infusion is effective for the long-term treatment of advanced PD patients and exerts a positive and clinically significant effect on motor complications with a relatively low dropout rate. [ABSTRACT FROM AUTHOR]

Duodenal levodopa infusion represents an effective strategy to manage motor and non-motor complications in patients with advanced Parkinson's disease (PD). However, most published clinical series regard small numbers of patients and do not exceed 1 year follow-up. In this multi-national observational cohort study conducted in seven specialised PD clinics and university hospitals we assessed long-term safety and outcome of chronic treatment with intra-duodenal levodopa infusions in a large population of patients with advanced PD. The starting population consisted of 98 treated patients (safety population). We report clinical outcomes of 73 patients with subsequent efficacy assessment(s) (efficacy population) over a follow-up period up to 2 years. Follow-up periods and collection of clinical observations varied based on individual routine care program. At last follow-up there was a significant ( p ≤ 0.05) reduction in duration of 'Off' periods as well as dyskinesia duration and severity that was associated with an improvement of quality of life. Twenty three patients (25.3 % of the safety population) withdraw, due to adverse drug reaction (5), procedure and device related events (7), compliance (3) and lack of efficacy (8). The mean duration for last value reported after baseline (LV) was 608 ± 292 days (median: 697 days). Our results demonstrate significant and sustained benefit over a long observation period in motor complications and in quality of life following a change from oral pulsatile to continuous levodopa delivery. The relatively large number of withdrawals reflects the current use of duodenal levodopa infusion in very advanced PD patients. [ABSTRACT FROM AUTHOR]

Motor complications of Parkinson's disease (PD) are a consequence of pulsatile dopaminergic stimulation from standard oral levodopa therapy. Levodopa-carbidopa intestinal gel (LCIG) is infused continuously via an intrajejunal percutaneous gastrostomy tube. This was the first study designed to characterize the full pharmacokinetic profiles of levodopa, carbidopa, and levodopa metabolite, 3-Omethyldopa (3-OMD) with 16-h LCIG infusion. Nineteen advanced PD patients (mean age, 65 years) who were on LCIG therapy for = 30 days were enrolled. Patients received their individualized LCIG infusion doses, and serial pharmacokinetic samples were collected. Eighteen patients completed the study; 19 were assessed for safety. Mean (SD) total levodopa and carbidopa doses were 1,580 (403) and 395 (101)mg, respectively. Mean (SD) Cavg (μg/mL) were 2.9 (0.84) for levodopa, 17.1 (4.99) for 3-OMD, and 0.22 (0.08) for carbidopa. The degree of fluctuation [defined as (Cmax-Cmin)/Cavg] in levodopa, 3- OMD, and carbidopa plasma concentrations was very low (0.52, 0.21, and 0.96, respectively) during hours 2-16 of infusion. Accordingly, the within-subject coefficients of variation in levodopa, 3-OMD, and carbidopa concentrations were low (13%, 6%, and 19%, respectively). Three patients (16%) reported =1 treatment-emergent adverse event; none were considered severe. Continuous intrajejunal LCIG infusion maintained stable plasma levodopa levels over 16 h. Consistent exposure has been shown to reduce motor and nonmotor complications associated with oral medications. LCIG was well tolerated, consistent with previous reports. [ABSTRACT FROM AUTHOR]

The treatment of the motor symptoms of Parkinson's disease (PD) is dependent on the use of dopamine replacement therapy in the form of l-dopa and dopamine agonist drugs. However, the development of dyskinesia (chorea, dystonia, athetosis) can become treatment limiting. The initiation of dyskinesia involves a priming process dependent on the presence of nigral dopaminergic cell loss leading to alterations in basal ganglia function that underlie the expression of involuntary movements following the administration of each drug dose. Once established, dyskinesia is difficult to control and it is even more difficult to reverse the priming process. Dyskinesia is more commonly induced by l-dopa than by dopamine agonist drugs. This has been associated with the short duration of l-dopa causing pulsatile stimulation of postsynaptic dopamine receptors compared to the longer acting dopamine agonists that cause more continuous stimulation. As a result, the concept of continuous dopaminergic stimulation (CDS) has arisen and has come to dominate the strategy for treatment of early PD. However, CDS has flaws that have led to the general acceptance that continuous drug delivery (CDD) is key to the successful treatment of PD. Studies in both experimental models of PD and in clinical trials have shown CDD to improve efficacy, but reduce dyskinesia induction, and to reverse established involuntary movements. Two key clinical strategies currently address the concept of CDD: (1) in early-, mid- and late-stage PD, transdermal administration of rotigotine provides 24 h of drug delivery; (2) in late-stage PD, the constant intraduodenal administration of l-dopa is utilized to improve control of motor symptoms and to diminish established dyskinesia. This review examines the rationale for CDD and explores the clinical benefit of using such a strategy for the treatment of patients with PD. [ABSTRACT FROM AUTHOR]

Motor complications impair quality of life and cause severe disability in patients with advanced Parkinson's disease (PD). Since they are often refractory to medical therapy, interventional therapies have been developed, which can provide a considerable reduction of daily off-time and dopaminergic dyskinesias. Continuous dopaminergic drug delivery (CDD) is based on the steady stimulation of striatal dopamine receptors by subcutaneous apomorphine or duodenal l-DOPA infusions via portable minipumps. Advances in the understanding of basal ganglia functioning and in neurosurgical, electrophysiological and neuroimaging techniques have led to a renaissance of neurosurgery for advanced PD. Deep brain stimulation of the subthalamic nucleus (STN-DBS) is the most invasive procedure promising great benefit and the highest level of independency for suitable patients, but is definitely associated with surgical risks and DBS-related side effects. Each of these more or less invasive therapy options has its own profile, and a thorough consideration of its advantages and drawbacks for the individual situation is mandatory. In this paper, we summarize relevant facts for this decision and provide some guidelines for a responsible counseling of eligible patients. [ABSTRACT FROM AUTHOR]

Abstract: We studied 19 patients (14 men, 5 women, Hoehn and Yahr (H&Y)≥3) with advanced Parkinson''s disease (PD) attending the Parkinson Institute, Milan, whose motor fluctuations and dyskinesia were not controlled by oral medications. After all oral PD medications had been withdrawn, they received a duodenal levodopa infusions (Duodopa, Solvay Pharmaceuticals) for 14h/day through a transabdominal port; levodopa boluses were administered in the morning and during “off” periods. The patients were evaluated by means of the UPDRS in the morning (“off”) and 60–120min after the infusion (“on”) at baseline and for a mean follow-up of 13.5±12.5months (up to 36months in 10 patients:). Levodopa (l-DOPA) and its metabolites were determined by HPLC with electrochemical detection. l-DOPA concentrations tended to higher in the afternoon (2008±345 vs 1713±274ng/mL) and correlated with the daily dose. O-methyldopa (OMD) levels correlated with l-DOPA levels, and the OMD/l-DOPA ratios were stable over the day. There was a relationship between decreasing UPDRS III scores and decreasing OMD/l-DOPA ratios. Dyskinesia (UPDRS IV, items 32–34) showed a clear improvement over time but there was no clear relationship with l-DOPA and OMD levels, or the OMD/l-DOPA ratio. The l-DOPA/dose ratio was stable over time, whereas OMD levels and the OMD/l-DOPA ratio decreased. It is conceivable that continuous infusion decreases metabolism possibly due to a reduction in methyl donor availability, as demonstrated by the increase in total homocysteine levels. Our results do not support the development of tolerance even after several months of continuous infusion, and indicate that pharmacodynamic factors play a role in afternoon off periods. [Copyright &y& Elsevier]

Abstract: Symptom control, daily “on” time, and quality of life (QoL) of nine patients with Advanced Parkinson''s Disease was assessed following 18-months treatment with Continuous Intraduodenal Levodopa Infusion (CIDLI). Patients had severe motor fluctuations and dyskinesias and had previously received treatment with oral levodopa and dopamine agonists. There were significant improvements in patients'' symptoms on the Unified Parkinson''s Disease Rating Scale, and QoL (Parkinson''s Disease QoL Questionnaire; Schwab & England Capacity for Daily Living Scale; p < 0.05). Mean (±SD) daily “on” time increased from 6.1 ± 1.9 to 12.0 ± 3.4 h (p < 0.05). Improved QoL in APD was associated with CIDLI-related improvements in symptom control and increase in daily “on” time. [Copyright &y& Elsevier]

Levodopa-carbidopa intestinal gel infusion (LCIG) is an established therapy for advanced Parkinson disease (PD), resulting in a significant improvement of quality of life. With increased LCIG adoption worldwide, potential complications due to abnormal vitamin absorption or metabolism have been reported in these patients. Neurologists are unfamiliar with vitamins physiology and pathophysiological mechanisms in case of their deficiency. Unfortunately, clinical and laboratory guidelines related to vitamin monitoring and supplementation in the context of treatment with LCIG are not available. We herein summarize the current knowledge on three vitamins that are reduced with LCIG therapy reporting on their physiology, laboratory testing, and clinical impact of their deficiency/excess. In addition, we proposed an opinion-based recommendation for clinicians treating LCIG patients. Patients and caregivers should be informed about the risk of vitamin deficiency. Vitamin B12, homocysteine, and methylmalonic acid (MMA) should be tested before starting LCIG, six months after and once/year thereafter. Vitamin B6 and folate testing is not universally available but it should be considered if homocysteine is elevated but MMA and/or total vitamin B12 are normal. Prophylaxis of vitamin deficiency should be started as soon as LCIG is implemented, possibly even before. Dietary recommendations are enough in most patients although a subgroup of patients is at higher risk and should receive Vitamin B12 regularly and cycles of B6. Finally, once diagnosed a vitamin deficiency should be readily treated and accompanied by clinical and laboratory monitoring. Resistant cases should receive non-oral routes of administration and possibly discontinue LCIG, even temporarily.

In patients with advanced Parkinson's disease, the continuous delivery to the small intestine via ajejunal tube of levodopa/carbidopa, formulated as a gel suspension (Duodopa) represents a new treatment method. The continuous release results in less variability in levodopa concentrations and fewer motor fluctuations and dyskinesias than with oral administration. The method which requires a very good collaboration between the neurologist and the gastroenterologist is used with increasing frequency in selected centres especially in severe patients. First, a classic PEG gastrostomy kit is placed under propofol sedation. This allows the passage of a pig tail catheter which is deployed in the jejunum and it is attached to a portable pump via a special tubing system. We present our experience of seven cases (5 males, mean age 60 years) with a follow up of one year. One patient died due to respiratory failure and aspiration pneumonia probably related to the endoscopic procedure. At one year, all patients agreed that the neurological benefit offsets the procedure related problems and the technical issues related to the enteral infusion system. [ABSTRACT FROM AUTHOR]