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| 2. |
- Aquilonius, Sten-Magnus, et al.
(author)
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Development of new levodopa treatment strategies in Parkinson’s disease – from bedside to bench to bedside
- 2017
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In: Upsala Journal of Medical Sciences. - 0300-9734 .- 2000-1967. ; 122:2, s. 71-77
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Research review (peer-reviewed)abstract
- This review will illustrate the process of moving from an idea through preclinical research and Galenic developments into clinical investigations and finally to approval by regulatory agencies within the European Union. The two new treatment strategies described, levodopa/carbidopa intestinal gel and levodopa/carbidopa microtablets, for advanced Parkinson's disease, have been developed in collaborative research within departments at Uppsala University. With this historical approach, reference priority is given to reports considered to be of special importance for this more than two decades long process from bedside to bench to bedside'.
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- Memedi, Mevludin, 1983-, et al.
(author)
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Construction of levodopa-response index from wearable sensors for quantifying Parkinson's disease motor functions
- 2016
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Conference paper (other academic/artistic)abstract
- The goal of this study was to investigate the feasibility of wrist worn motion sensors to objectively measure motor functions in Parkinson’s disease (PD). More specifically, the aim was to construct a sensor-based levodopa-response index (SBLRI) and evaluate its clinimetric properties (convergent validity and internal consistency). Nineteen advanced PD patients and 22 healthy controls were recruited in a single center, open label, single dose clinical trial in Sweden. The subjects performed standardized motor tasks while wearing one sensor on each wrist and one on each ankle. Each sensor unit consisted of three-dimensional accelerometer and gyroscope. The patients were video recorded and the videos were blindly rated by three independent movement disorder specialists. The clinical scores were given using the Treatment Response Scale (TRS) on a scale from -3 = ‘Very Off’ to 0 = ‘On’ to +3 = ‘Very dyskinetic’. The clinical assessments were based on the overall motor function of the patients. A mean TRS was defined as the mean of the three specialists’ assessments per time point. The measurements were repeated over several time points following a single levodopa/carbidopa morning dose (50% over normal to induce dyskinesias). Sensor measurements during rapid alternating movements of hands were processed with time series analysis methods to calculate spatiotemporal parameters designed to measure bradykinesia and dyskinesia. For each hand, 96 spatiotemporal parameters were calculated and their average scores were then used in a principal component analysis to reduce the dimensionality by retaining 6 principal components. These components were then used as predictors to support vector machines and to be mapped to the mean TRS ratings of the three specialists and to calculate the SBLRI. For this analysis, a 10-fold stratified cross-validation was performed. The SBLRI was strongly correlated to mean TRS with a Pearson correlation coefficient of 0.79 (CI: 0.74-0.83, p<0.001). The 95% confidence interval for the mean squared error of SBLRI on patients data was ± 1.62 with a mean value of 0.57 whereas on healthy controls data was ± 1 with a mean value of 0.27. The sensor-based spatiotemporal parameters had good internal consistency with a Cronbach’s Alpha coefficient of 0.87 and significantly differed between patients and healthy controls. The results demonstrated that the SBLRI had good clinimetric properties for measuring motor functions (Off and dyskinesia) in PD patients. The method could also distinguish hand rotation movements exhibited by patients from those exhibited by healthy controls. The SBLRI provides effect-time profiles, which could be useful during therapy individualization of advanced PD patients.
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| 7. |
- Senek, Marina, et al.
(author)
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Levodopa/carbidopa microtablets in Parkinson disease : pharmacokinetics and blinded motor assessment
- 2016
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In: Twentieth International Congress of Parkinson's Disease and Movement Disorders.
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Conference paper (other academic/artistic)abstract
- The aim of this study was to characterize the levodopa and carbidopa plasma concentration in relation to blinded motor function ratings. This is a part of a study where a Multimodal motor Symptoms Quantification (MuSyQ) platform consisting of three different types of sensors were tested while evoking motor fluctuations with levodopa/carbidopa(LD/CD) microtablets in fluctuating Parkinson’s disease (PD) patients. Today, dose titration and chronic treatment largely relies on the patient’s subjective assessment of symptoms and clinicians’ assessment of patient status during a visit at the clinic. This was a single-center, open-label, single dose study in patients experiencing motor fluctuations. Patients were given 150% of their individual levodopa equivalent morning dose. Blood sampling and motor function testing were conducted for up to 6.5 hours at prespecified time points. The patients performed standardized motor activities for clinical rating in accordance with parts of the Unified Parkinson’s disease Rating Scale (UPDRS) and Unified Dyskinesia RatingScale (UDysRS). Each test cycle was video recorded, and the video sequences were presented to three movement disorder specialists in a randomized order for blinded rating of UPDRS items and the treatment response scale (TRS). Concentration versus time profiles and the pharmacokinetics were compared with a study previously conducted in healthy subjects. Nineteen patients, 14 male and 5 female, were included in the study. The individual LD/CD doses ranged between 110/27.5mg to 410/102.5 mg. The concentration time profiles are similar to the LD/CD microtablet profiles reported in healthy subjects. The blinded video ratings managed to capture the most distinctive movements. This is the first pharmacokinetic study where patients received LD/CD microtablets. For patients fluctuating from 'off' to dyskinetic, the relationship between the plasma concentration and motor function was clearer compared to the patients that fluctuated to a lesser extent.
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| 8. |
- Senek, Marina, et al.
(author)
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Levodopa/carbidopa microtablets in Parkinson's disease : a study of pharmacokinetics and blinded motor assessment
- 2017
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In: European Journal of Clinical Pharmacology. - Heidelberg, Germany : Springer. - 0031-6970 .- 1432-1041 .- 0014-2999. ; 73:5, s. 563-571
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Journal article (peer-reviewed)abstract
- Background: Motor function assessments with rating scales in relation to the pharmacokinetics of levodopa may increase the understanding of how to individualize and fine-tune treatments.Objectives: This study aimed to investigate the pharmacokinetic profiles of levodopa-carbidopa and the motor function following a single-dose microtablet administration in Parkinson’s disease.Methods: This was a single-center, open-label, single-dose study in 19 patients experiencing motor fluctuations. Patients received 150% of their individual levodopa equivalent morning dose in levodopa-carbidopa microtablets. Blood samples were collected at pre-specified time points. Patients were video recorded and motor function was assessed with six UPDRS part III motor items, dyskinesia score, and the treatment response scale (TRS), rated by three blinded movement disorder specialists.Results: AUC0–4/dose and Cmax/dose for levodopa was found to be higher in Parkinson’s disease patients compared with healthy subjects from a previous study, (p = 0.0008 and p = 0.026, respectively). The mean time to maximum improvement in sum of six UPDRS items score was 78 min (±59) (n = 16), and the mean time to TRS score maximum effect was 54 min (±51) (n = 15). Mean time to onset of dyskinesia was 41 min (±38) (n = 13).Conclusions: In the PD population, following levodopa/carbidopa microtablet administration in fasting state, the Cmax and AUC0–4/dose were found to be higher compared with results from a previous study in young, healthy subjects. A large between subject variability in response and duration of effect was observed, highlighting the importance of a continuous and individual assessment of motor function in order to optimize treatment effect.
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| 10. |
- Senek, Marina, et al.
(author)
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Motor fluctuations in relation to plasma concentrations following a single-dose of levodopa/carbidopa microtablets in advanced Parkinson's disease
- 2016
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Conference paper (other academic/artistic)abstract
- Objective: The aim of this study was to characterize the levodopa and carbidopa plasma concentration in relation to blinded motor function ratings. This is a part of a study where a Multimodal motor Symptoms Quantification (MuSyQ) platform consisting of three different types of sensors were tested while evoking motor fluctuations with levodopa/car-bidopa (LD/CD) microtablets in fluctuating Parkinson’s disease (PD) patients.Background: Today, dose titration and chronic treatment largely relies on the patient’s subjective assessment of symptoms and clinicians’ assessment of patient status during a visit at the clinic.Methods: This was a single-center, open-label, single dose study in patients experiencing motor fluctuations. Patients were given 150% of their individual levodopa equivalent morning dose. Blood sampling and motor function testing were conducted for up to 6.5 hours at prepecified time points. The patients performed standardized motor activities for clinical rating in accordance with parts of the Unified Parkinson’s disease Rating Scale (UPDRS) and Unified Dyskinesia Rating Scale (UDysRS). Each test cycle was video recorded, and the video sequences were presented to three movement disorder specialists in a randomized order for blinded rating of UPDRS items and the treatment response scale (TRS). Concentration versus time profiles and the pharmacokinetics were compared with a study previously conducted in healthy subjects.Results: Nineteen patients, 14 male and 5 female, were included in the study. The individual LD/CD doses ranged between 110/27.5 mg to 410/102.5 mg. The concentration time profiles are similar to the LD/CD microtablet profiles reported in healthy subjects. The blinded video ratings managed to capture the most distinctive movements.Conclusions: This is the first pharmacokinetic study where patients received LD/CD microtablets. For patients fluctuating from ‘off’ to dyskinetic, the relationship between the plasma concentration and motor function was clearer compared to the patients that fluctuated to a lesser extent.
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