Bredberg E, Nilsson D, Johansson K, Aquilonius SM, Johnels B, Nystrom C, Paalzow L.
Intraduodenal infusion of a water-based levodopa dispersion for optimisation of the therapeutic effect in severe Parkinson’s disease.
Eur J Clin Pharmacol 1993;45(2)
SYNOPSIS
This is the first study of the Duodopa principle. Milled Sinemet (levodopa/carbidopa, 4:1) tablets were dispersed in a 1.8% aqueous solution of methylcellulose dispensed in 50- or 100?ml cassettes. The levodopa concentration was 20 mg/ml. This formulation was used for intraduodenal infusion via a nasoduodenal tube by a portable pump. The objectives of the study were to compare 2 modes of levodopa administration, oral tablets versus intraduodenal infusion, with regard to variability in plasma levodopa concentrations over 9 hours, variability in motor activities by the PLM test (see below) and video scoring of “on-off” motor fluctuations. Two (2) nonconsecutive test days on each treatment were studied due to the known day-to-day variation of these measures in advanced Parkinson’s disease. The study was not blinded.
Patient Characteristics
Five (5) male and 1 female patient, aged between 55 and 68 years, with duration of disease between 10 and 20 years, and with an off-drug Hoehn and Yahr stage of 4–5 participated in the study. The daily dose of levodopa at baseline ranged from 300 to 2500 mg with tablet intake every 2–3 hours. Three (3) of the patients used concomitant antiparkinson medication with selegiline, orphenadrine, and/or amantadine.
Procedures
The patients were considered to be on optimal oral therapy with Sinemet tablets, in some cases, in combination with other antiparkinson medication. Baseline testing on 2 nonconsecutive days was performed as described below. Six (6) weeks later, the patients were again tested on 2 nonconsecutive days after 1 week’s optimization on intraduodenal infusion of the levodopa/carbidopa dispersion. The correct location of the intraduodenal tube was checked by X-ray at each test day.
Assessment Methods Plasma levodopa concentrations were measured every 15 minutes between 8 and 5 p.m. on each test day in order to determine its variability (SD) from the mean. Motor function was assessed by the PLM test (Posturo-Locomotor-Manual test) using an opto-electronic system that permits automatic analysis of total movement time, time to straighten the body, time for forward locomotion, and the time for arm elevation while the patients perform a series of actions as fast as possible. Finally, the patients were video recorded while performing a fixed set of movements (rising from chair, walking, “piano playing” and alternating hand movements) and rated for “on-off” motor fluctuations using a rating scale running from -2 (“off”) to 0 (“on”) to +2 (“on” with dyskinesia).
Results Plasma levodopa concentrations varied 3–10 fold during oral therapy, while a more stable concentration was obtained during infusion. The average intraindividual coefficient of variation for the plasma concentrations of levodopa following oral administration was 45 (±16) % and 12 (±5) % during intraduodenal infusion. The relative bioavailability of oral compared to intraduodenal levodopa was about 100% in all patients. The dispersion was stable with respect to both levodopa and carbidopa concentrations during the 1-week test.
Motor function as assessed both with the PLM test and video scoring showed less “on-off” fluctuations during the week with intraduodenal levodopa as compared to oral medication.
Conclusion
Intraduodenal infusion of a concentrated dispersion of levodopa resulted in more stable plasma concentrations of levodopa over 9 hours as compared with oral tablet intake every 2–3 hours. As a result, “on-off” motor fluctuations and dyskinesia were reduced, with more time in a near normality state during the day.
Continuous Intraduodenal Levodopa/Carbidopa Infusion in Patients with Advanced Parkinson’s Disease.
Study Report No. NPP-001-92. 1999.
SYNOPSIS
Seven (7) patients with advanced Parkinson’s disease and persistent levodopa-carbidopa associated motor fluctuations (on-off, dyskinesia) on the best possible anti-Parkinson medication according to their neurologist were switched from oral to intraduodenal infusion of levodopa-carbidopa. The objective of the study was to test the hypothesis that a stable plasma concentration over time would provide continuous dopamine receptor stimulation (CDS) and result in less motor fluctuations. It should be noted that motor fluctuations in patients with severe Parkinson’s disease vary unpredictably from day to day, which makes these phenomena difficult to study. Therefore, means or medians of the results from two (or more) assessment days in one condition have been compared with similar means or medians in another condition.
Patient Characteristics
Male (n=6) and female (n=1) patients with early onset Parkinson’s disease were included. Age range: 47–69 years; duration of Parkinson’s disease: 10–26 years; time on oral levodopa/carbidopa: 6–21 years; dose range 500–2500 mg daily. Duration of motor fluctuations: 3–17 years. The severity of disease ranged between 3 and 5 according to Hoehn & Yahr.
Procedures
Baseline assessments (see Assessment Methods) on two nonconsecutive days were done on the current medication with oral levodopa. The patients were again tested on two nonconsecutive days while on intraduodenal levodopa via a nasoduodenal tube with their concomitant anti-Parkinson’s disease medication. Thereafter, a permanent intraduodenal tube was inserted via gastrotomy and the patients were again tested on two nonconsecutive days at 1, 3, and 6 months after surgery (n=7) or at 8, 10, 18, and 31 months (n=2) while on continuous intraduodenal levodopa/carbidopa medication. The intraduodenal levodopa/carbidopa formulation was a water-based dispersion of the two compounds (20 mg/ml levodopa and 5 mg/ml carbidopa) in methylcellulose. The correct placement of the catheter tip was checked by X-ray before each testing occasion.
Assessment Methods
The main method used to assess percentage time “on” with no or minimal dyskinesia was video filming the patients when performing a standardized sequence of motor tasks (“piano playing,” alternating hand movements, rising from a chair and walking) every 30 minutes for 9–11 hours. These films were used to score motor performance on a rating scale from -3 to 0 to +3, where -3 and -2 was defined as “off”, -1, 0 and +1 as “normal” (on without dyskinesia) and +2 and +3 as “hyperkinesia” (on with hyper-/dyskinesia). The time spent in different motoric states on oral therapy and on infusion therapy at all test occasions were compared.
Other methods used were the PLM test (an automatic opto-electronic system measuring total movement time, and a Postural, a Locomotor, and a Manual phase can be assessed), UPDRS, ADL test and a patient self-rating scale performed at home.
Results
The PLM test demonstrated that patients performed faster on infusion than on oral therapy. As compared to the second day on oral therapy, movement time decreased significantly (P = 0.05) on both the first and second day on infusion. Also the variances in movement time decreased on infusion compared to oral therapy (P = 0.001).
Ratings from the video films are in accordance with the PLM test results as the patients spent more time in “normal” motoric state on infusion, less time in both “off” state and "hyperkinetic" as compared to corresponding figures on oral therapy.
According to the historical data of the UPDRS, Parts I and II, obtained for oral treatment as compared to the last test occasion on infusion, five of the seven patients subjectively improved. Six/seven (6/7) had fewer complications (dyskinesia, dystonia, and fluctuations) due to therapy.
No increase in severity, according to Hoehn and Yahr rating of the disease, was observed after the 6 months of intraduodenal treatment.
There was no major complication or severe adverse event which could be attributed to the infusion of Duodopa. All patients experienced a general improvement after the introduction of continuous treatment and did not want to return to oral therapy in spite of the expected inconvenience in carrying a pump.
Conclusion
Continuous intraduodenal infusion of levodopa is an alternative treatment strategy for patients with advanced Parkinson’s disease when conventional therapy has failed.
Nilsson D, Hansson LE, Johansson K, Nyström C, Paalzow L, Aquilonius SM.
Long-term intraduodenal infusion of a water based levodopa-carbidopa dispersion in very advanced Parkinson’s disease.
Acta Neurol Scand 1998;97:175–183.
Note: This publication reports long-term results of 2 separate cases in addition to 7 cases from Study Report No. NPP-001-92.
SYNOPSIS
Nine (9) patients with advanced Parkinson’s disease and persistent levodopa-carbidopa associated motor fluctuations (on-off, dyskinesia) on the best possible anti-Parkinson medication according to their neurologist were switched from oral to intraduodenal infusion of levodopa-carbidopa. The objective of the study was to test the hypothesis that a stable plasma concentration over time would provide continuous dopamine receptor stimulation (CDS) and result in less motor fluctuations. It should be noted that motor fluctuations in patients with severe Parkinson’s disease vary unpredictably from day to day, which makes these phenomena difficult to study. Therefore, means or medians of the results from two (or more) assessment days in one condition have been compared with similar means or medians in another condition.
Patient Characteristics
Male (n=8) and female (n=1) patients with early onset Parkinson’s disease were included. Age range: 47–69 years; duration of Parkinson’s disease: 10–26 years; time on oral levodopa/carbidopa: 6–21 years; dose range 500–2500 mg daily. Duration of motor fluctuations: 3–17 years. Three (3) patients had no concomitant anti-Parkinson’s disease medication; 6 patients were on bromocriptine (dopamine receptor agonist), 3 on selegiline, and 1 on orphenadrine. All patients had tried various concomitant anti-Parkinson’s disease medications in the past with no or minimal improvement. Three (3) patients had undergone brain surgery with thalamotomy without (persisting) improvement. The severity of disease ranged between 3 and 5 according to Hoehn & Yahr.
Procedures
Baseline assessments (see Assessment Methods) on two nonconsecutive days were done on the current medication with oral levodopa. The patients were again tested on two nonconsecutive days while on intraduodenal levodopa via a nasoduodenal tube with their concomitant anti-Parkinson’s disease medication. Thereafter, a permanent intraduodenal tube was inserted via gastrotomy and the patients were again tested on two nonconsecutive days at 1, 3, and 6 months after surgery (n=7) or at 8, 10, 18, and 31 months (n=2) while on continuous intraduodenal levodopa/carbidopa medication. The intraduodenal levodopa/carbidopa formulation was a water-based dispersion of the two compounds (20 mg/ml levodopa and 5 mg/ml carbidopa) in methylcellulose. The correct placement of the catheter tip was checked by X-ray before each testing occasion.
Assessment Methods
The main method used to assess percentage time “on” with no or minimal dyskinesia was video filming the patients when performing a standardized sequence of motor tasks (“piano playing,” alternating hand movements, rising from a chair and walking) every 30 minutes for 9–11 hours. These films were used to score motor performance on a rating scale from -3 to 0 to +3, where -3 and -2 was defined as “off”, -1, 0 and +1 as “normal” (on without dyskinesia) and +2 and +3 as “Hyperkinesia” (on with hyper-/dyskinesia). The time spent in different motoric states on oral therapy and on infusion therapy at all test occasions were compared.
Other methods used were the PLM test (an automatic opto-electronic system measuring total movement time, and a Postural, a Locomotor, and a Manual phase can be assessed), UPDRS, ADL test, and a patient self-rating scale performed at home. Plasma concentrations of levodopa were measured every 15 minutes during waking hours in 2 patients.
Results
The video scoring results were as follows:
Patients
Route of Administration
Off
Normal
Hyperkinetic
A-B
oral
54
9
38
intraduodenal
31
35
34
C-I
oral
17
30
53
intraduodenal
12
54
34
Patients A and B were pilot cases followed up to 31 months and provided pharmacokinetic data showing significantly less variability in plasma levodopa concentrations with duodenal Duodopa as compared with oral treatment with levodopa/carbidopa.
Patients C – I followed the main assessment procedure up to 6 months.
The PLM tests showed that the total movement time and the variance in motor performance decreased statistically significantly on intraduodenal administration as compared with oral treatment both in Patients A and B, and in patients C – I.
According to the UPDRS, 5 out of 7 patients (Patients C – I) improved in Mentation, Behavior, Mood, and ADL over 6 months and 6 out of the 7 had fewer motor complications.
According to the patients’ global assessments, 3/7 improved and 4/7 were unchanged when at “best,” 4/7 were improved, 1/7 was unchanged, and 2/7 deteriorated when at “worst.”
The outcome of the pharmacokinetic analyses in Patients A and B showed that the mean plasma levodopa concentration was lower on long-term intraduodenal infusion than on oral therapy. Also, the variance in plasma levodopa concentrations decreased statistically significantly.
Conclusion
Continuous intraduodenal infusion of levodopa is an alternative treatment strategy for patients with advanced Parkinson’s disease when conventional therapy has failed.
A Retrospective Study on Patients treated with DuodopaÒ/Duodopa® N from January 1st, 1991, to December 31st, 1999.
Study Report No. NPP-002-00. 2000.
Nyholm D, Aquilonius SM. Intestinal infusion of Duodopa®—eight years’ experience. Parkinsoni
Note: This report describes results of 31 cases (6 from Study Report No. NPP-001-92; 2 as reported in Nilsson et al., 1998; and an additional 23 cases).
SYNOPSIS
The total number of patients with idiopathic Parkinson’s disease who had ever received Duodopa until 31st December 1999 was 34. In this follow-up investigation on intraduodenal infusion, 31 consecutive patients gave their informed consent to participate. Patient No. 34 had never received intraduodenal infusion of levodopa and was, therefore, not included in the study. Patient Nos. 32 and 33 did not sign their informed consent and were not included in the study.
Patient Characteristics
The 31 patients, 20 males and 11 females, included had a median age of 63 years (range:
47–76 years). Their median duration of illness was 19 years (range: 9–31 years).
Procedures
This investigation was performed by reviewing hospital medical records from the start of Duodopa infusion therapy up until the census date.
Assessment Methods
Documentation of the duration of treatment time, interruptions, and discontinuations was recorded. An interruption in treatment was defined as a 24?h withdrawal of the intraduodenal infusion.
Results The treatment time on Duodopa ranged from 15 days to 3115 days (8 years, 7 months). The median treatment time was 1340 days (3 years, 8 months). The total treatment time was 44,084 days (i.e., 120 years and 9 months).
Technical problems causing interruption in treatment have so far happened to less than half of the patients (14 out of 31). Reasons for interruption: dislocation of the tip of the tube from the duodenum into the stomach (n=8), occlusion of tube (n=7), evaluation of efficacy as compared to oral therapy (n=5), changing of tube (n=4), pump dysfunction (n=2), and medication not distributed to patient’s home (n=2).
Nine (9) patients had discontinued the treatment with Duodopa permanently for various reasons: dementia, confusion, anxiety (n=3), repeated tube dislocations (n=3), Parkinson-plus development (n=1), gastric pain (n=1), and general health impairment (n=1).
Conclusions
Continuous intraduodenal infusion of levodopa is a treatment strategy suitable for long-term use. There have been a few technical complications and no severe or serious adverse events.
Nilsson D, Nyholm D, Aquilonius SM. Duodenal levodopa infusion in Parkinson’s disease—long-term experience.
Acta Neurol Scand 2001. 104;6:343–348.
Note: This publication describes long-term results of 28 cases (26 from Study Report No. NPP?002?00, 1 from Study Report No. NPP-001-92, and 1 additional case)
SYNOPSIS
The present publication is a follow-up study for 2–83 months of 28 patients with advanced Parkinson’s disease and persistent levodopa-carbidopa associated motor fluctuations (on-off, dyskinesia) on the best possible anti-Parkinson medication according to their neurologist that had been switched from oral to intraduodenal infusion of Duodopa. Nine (9) of the first treated patients were followed with repeated tests of motor fluctuations for up to 7 years.
Patient Characteristics
Male (n=18) and female (n=10) patients with advanced Parkinson’s disease with early onset were included. Age range at debut of Parkinson’s disease: 33–68 years; duration of Parkinson’s disease at surgery: 6–26 years; daily levodopa dose range (oral): 475–3100 mg. Twenty-one (21) patients used concomitant anti-Parkinson’s disease medication (dopamine agonists, MAO-B inhibitors, and anticholinergics) at the time before infusions started. At the long-term follow-up (2–83 months), only 12 patients were treated with concomitant anti-Parkinson’s disease drugs.
Procedures
Baseline assessments (see Assessment Methods) on two nonconsecutive days were done on the current medication with oral levodopa. The 9 patients (A-I) were again tested on two nonconsecutive days while on intraduodenal levodopa after 3–8 months and after 4–7 years, some still using concomitant anti-Parkinson’s disease medication. The intraduodenal levodopa/carbidopa formulation was a water-based dispersion of the two compounds (20 mg/ml levodopa and 5 mg/ml carbidopa) in methylcellulose. The correct placement of the catheter tip was checked by X-ray before each testing occasion.
Assessment Methods The main method used to assess variability in mobility was the PLM test (an automatic opto-electronic system measuring total movement time, and a Postural, a Locomotor, and a Manual phase can be assessed). This test was applied every 15–20 minutes for 9–11 hours.
The method used to assess percentage time “on” with no or minimal dyskinesia was video filming the patients when performing a standardized sequence of motor tasks (“piano playing,” alternating hand movements, rising from a chair and walking) every 30 minutes for 9–11 hours. These films were used to score motor performance on a rating scale from -3 to 0 to +3, where -3 and -2 was defined as “off”, -1, 0 and +1 as “normal” (on without dyskinesia), and +2 and +3 as “Hyperkinesia” (on with hyper-/dyskinesia). The time spent in different motor states on oral therapy and on infusion therapy at all test occasions were compared.
Further, disease-specific disability scales were used: Unified Parkinson’s Disease Rating Scale, Webster Rating Scale, and North Western University Disability Scale.
Results
Total experience of intraduodenal infusions with Duodopa was 1045 months (87 patient-years). Some technical problems with pumps and tubes are reported but no severe or serious adverse events.
The results from PLM-test and video recordings comparing oral medication with 3–8 months of infusion were presented in Nilsson et al., 1998. Some patients were unable to perform the follow-up for different reasons such as curtailed treatment, severe orthostatism, and severe kyphosis.
PLM-test results regarding median movement time (MT) and MT variance (n=5):
Median movement time, oral therapy versus 4–7 years of continuous infusion therapy—When comparing the first test day, moving time was significantly decreased in 2/5 and unchanged in the other 3 patients after 4–7 years. When comparing the second test day, moving time was significantly decreased in 3/5, unchanged in 1/5, and significantly increased in 1/5.
Median movement time, 3–8 months versus 4–7 years of continuous infusion therapy—2/5 showed significant moving time improvement on both test days, 1/5 showed no significant differences, whereas 1/5 significantly increased his moving time both test days after 7 years. Finally, 1/5 significantly increased moving time on the first test day and had a nonsignificant slightly increased moving time the second day after 7 years.
Movement time variance—The moving time variance at 4–7 years of infusion as compared to oral therapy was significantly decreased both days in 1/5 and one day in 1/5. The variance was significantly increased both days in 1/5 and one of the days in 1/5. The last patient had no significant differences in variance between oral therapy and 4 years infusion follow-up. The moving time variance at 4–7 years as compared to 3–8 months of infusion was significantly decreased on one of the days in 1/5, significantly increased both days in 1/5 and one of the days in 2/5, whereas the other days did not show any significant differences.
Video Scoring Results:
Ratings from videotapes indicate an improvement with substantially more time spent in a near normal state as compared to oral therapy after 4–7 years of the new treatment. The mean time spent in “off” state after 4–7 years had increased as compared to the two earlier occasions, mainly because one patient had difficulties walking and, therefore, was scored as “off” at every recording. The dyskinesias were decreased after 3–8 months of duodenal as compared to oral therapy and even further decreased after 4–7 years.
Conclusion
Continuous intraduodenal infusion of levodopa is an alternative long-term treatment strategy for patients with advanced Parkinson’s disease when conventional therapy has failed.
A Comparative Pharmacokinetic Study of Continuous Intraduodenal L-dopa/Carbidopa Infusion in Patients with Advanced Parkinson’s Disease.
Study Report No. NPP-001-99. 2000.
Nyholm D, Askmark H, Knutson T, Gomes-Trolin C, Nystrom C, Aquilonius SM. Con
SYNOPSIS
Twelve (12) patients suffering from advanced idiopathic Parkinson’s disease and diurnal motor fluctuations in spite of optimised oral treatment with levodopa participated in the study. The patients were switched from previous anti-Parkinson’s disease drugs (including levodopa/carbidopa and any concomitant anti-Parkinson’s disease medication) to oral Sinemet Depot given every 3 hours during waking hours. During the study, no concomitant anti-Parkinson’s disease medication (e.g., COMT inhibitors, dopamine agonists, anticholinergics) was allowed. A crossover design was used with one group of patients starting with oral therapy for 3 weeks, thereafter being switched to intraduodenal infusion with Duodopa. The other group started with Duodopa and was then switched to oral treatment. During the first week of each period, the patients were optimised on the respective treatment. The patients were not blinded to treatment.
Patient Characteristics
Male (n=10) and female (n=2) patients, aged 39–76 years of age, with an onset of Parkinson’s disease at age 31–59 years and with a duration of levodopa treatment of 4–26 years. The severity of Parkinson’s disease “at worst” was 3–5 according to Hoehn & Yahr. The daily levodopa dose ranged from 475–1350 mg and 10 out of the 12 patients were on concomitant anti-Parkinson’s disease medication (COMT inhibitor or dopamine agonists) before entrance to the study. Most patients had tried various anti-Parkinson’s disease drug combinations in the past without improvement of their motor fluctuations. All patients suffered “off” periods at least 25% of the day, and dyskinesia at least 25% of the day according to Questions 39 and 32, respectively, on the UPDRS.
Procedures
Measurement of plasma levodopa concentrations at 30?minute intervals between 8 a.m. and 5 p.m. and determination of its variability on oral Sinemet Depot versus Duodopa was the primary objective of the study. The laboratory performing the determination of plasma levodopa concentrations was blind to the treatments. Clinically, the patients were studied with the PLM (Posture, Locomotion, and Manual performance) test and video recorded while performing a series of activities every 60 minutes throughout the day. Motor performance was scored with a rating scale ranging from -3 to +3, where -3 represented severe parkinsonism (“off”), 0 normal (“on”), and + 3 “on” with severe dyskinesia. Withdrawal of blood samples, the PLM test, video recording, and adverse event questioning were done at baseline and at 3 separate days during each treatment period. UPDRS was scored at baseline and the end of Weeks 3 and 6. The severity of Parkinson’s disease was assessed according to Hoehn & Yahr at inclusion and at the end of the study.
Results
There was no difference in mean plasma levodopa concentrations between treatments. With regard to daily within-patient variance and coefficient of variations, the differences between treatments were statistically significant in favor of Duodopa. The results from the PLM test showed no statistically significant differences between treatments due to skewed distribution of data.
The results from ratings on the Parkinsonism–Dyskinesia scale, the patients on Duodopa spent more time in the “on” state, less time in the “off” state as well as in the dyskinetic state. These differences in favor of Duodopa were statistically significant. There were no statistically significant changes in UPDRS or in Hoehn & Yahr staging of the disease during the study. A number of adverse events were recorded, which were considered to be expected in a group of patients suffering from severe Parkinson’s disease. One serious adverse event occurred (heart arrhythmia). Except for nasopharnyngeal irritation in one patient due to the nasoduodenal tube, all patients tolerated the daily intraduodenal infusions of Duodopa for 3 weeks.
Conclusion
Patients on constant intraduodenal infusion of Duodopa showed less variability in plasma levodopa concentrations than on oral levodopa/carbidopa tablets given every 3 hours during the day. This difference in plasma kinetics of levodopa was associated with less motor fluctuations according to ratings of observed motor behaviors from video recordings. The PLM test failed to show difference between the two routes of administration due to skewed distribution of data. There were no reports indicating gastrointestinal intolerance to the intraduodenal infusions of Duodopa over 3 weeks.
