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  • 1. Aghanavesi, S
    et al.
    Bergquist, F
    Nyholm, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Senek, Marina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Memedi, M
    Motion Sensor-Based Assessment of Parkinson's Disease Motor Symptoms During Leg Agility Tests: Results From Levodopa Challenge2020In: IEEE journal of biomedical and health informatics, ISSN 2168-2194, E-ISSN 2168-2208, Vol. 24, no 1, p. 111-119Article in journal (Refereed)
    Abstract [en]

    Parkinson's disease (PD) is a degenerative, progressive disorder of the central nervous system that mainly affects motor control. The aim of this study was to develop data-driven methods and test their clinimetric properties to detect and quantify PD motor states using motion sensor data from leg agility tests. Nineteen PD patients were recruited in a levodopa single dose challenge study. PD patients performed leg agility tasks while wearing motion sensors on their lower extremities. Clinical evaluation of video recordings was performed by three movement disorder specialists who used four items from the motor section of the unified PD rating scale (UPDRS), the treatment response scale (TRS) and a dyskinesia score. Using the sensor data, spatiotemporal features were calculated and relevant features were selected by feature selection. Machine learning methods like support vector machines (SVM), decision trees, and linear regression, using ten-fold cross validation were trained to predict motor states of the patients. SVM showed the best convergence validity with correlation coefficients of 0.81 to TRS, 0.83 to UPDRS #31 (body bradykinesia and hypokinesia), 0.78 to SUMUPDRS (the sum of the UPDRS items: #26-leg agility, #27-arising from chair, and #29-gait), and 0.67 to dyskinesia. Additionally, the SVM-based scores had similar test-retest reliability in relation to clinical ratings. The SVM-based scores were less responsive to treatment effects than the clinical scores, particularly with regards to dyskinesia. In conclusion, the results from this study indicate that using motion sensors during leg agility tests may lead to valid and reliable objective measures of PD motor symptoms.

  • 2.
    Ilias, Thomas
    et al.
    Dalarna Univ, S-79131 Falun, Sweden..
    Filip, Bergquist
    Gothenburg Univ, S-40530 Gothenburg, Sweden..
    Radu, Constantinescu
    Gothenburg Univ, S-40530 Gothenburg, Sweden..
    Nyholm, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Senek, Marina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Mevludin, Memedi
    Dalarna Univ, S-70281 Orebro, Sweden.;Orebro Univ, S-70281 Orebro, Sweden..
    Using measurements from wearable sensors for automatic scoring of Parkinson's disease motor states: results from 7 patients2017In: 2017 39th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), IEEE , 2017, p. 131-134Conference paper (Refereed)
    Abstract [en]

    The objective of this study was to investigate the validity of an objective gait measure for assessment of different motor states of advanced Parkinson's disease (PD) patients. Seven PD patients performed a gait task up to 15 times while wearing sensors on their upper and lower limbs. Each task was performed at specific points during a test day, following a single dose of levodopa-carbidopa. At the time of the tasks the patients were video recorded and three movement disorder experts rated their motor function on three clinical scales: a treatment response scale (TRS) that ranged from -3 (very bradykinetic) to 0 (ON) to +3 (very dyskinetic), a dyskinesia score that ranged from 0 (no dyskinesia) to 4 (extreme dyskinesia), and a bradykinesia score that ranged from 0 (no bradykinesia) to 4 (extreme bradykinesia). Raw accelerometer and gyroscope data of the sensors were processed and analyzed with time series analysis methods to extract features. The utilized features quantified separate limb movements as well as movement symmetries between the limbs. The features were processed with principal component analysis and the components were used as predictors for separate support vector machine (SVM) models for each of the three scales. The performance of each model was evaluated in a leave-one-patient out setting where the observations of a single patient were used as the testing set and the observations of the other 6 patients as the training set. Root mean square error (RMSE) and correlation coefficients for the predictions showed a good ability of the models to map the sensor data into the rating scales. There were strong correlations between the SVM models and the mean ratings of TRS (0.79; RMSE=0.70), bradykinesia score (0.79; RMSE=0.47), and bradykinesia score (0.78; RMSE=0.46). The results presented in this paper indicate that the use of wearable sensors when performing gait tasks can generate measurements that have a good correlation to subjective expert assessments.

  • 3. Johansson, Dongni
    et al.
    Ericsson, Anders
    Johansson, Anders
    Medvedev, Alexander
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Systems and Control. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Automatic control.
    Nyholm, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Ohlsson, Fredrik
    Senek, Marina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Spira, Jack
    Thomas, Ilias
    Westin, Jerker
    Bergquist, Filip
    Individualization of levodopa treatment using a microtablet dispenser and ambulatory accelerometry2018In: CNS Neuroscience & Therapeutics, ISSN 1755-5930, E-ISSN 1755-5949, Vol. 24, no 5, p. 439-447Article in journal (Refereed)
  • 4.
    Johansson, Dongni
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Clin Neurosci, Gothenburg, Sweden.
    Thomas, Ilias
    Dalarna Univ, Dept Microdata Anal, Falun, Sweden.
    Ericsson, Anders
    RISE Acreo, Gothenburg, Sweden;Karolinska Inst, Dept Clin Neurosci, Neurol, Stockholm, Sweden.
    Johansson, Anders
    Medvedev, Alexander
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Automatic control. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Systems and Control.
    Memedi, Mevludin
    Orebro Univ, Sch Business, Informat, Orebro, Sweden.
    Nyholm, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Ohlsson, Fredrik
    RISE Acreo, Gothenburg, Sweden.
    Senek, Marina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Spira, Jack
    Sensidose AB, Sollentuna, Sweden.
    Westin, Jerker
    Dalarna Univ, Dept Microdata Anal, Falun, Sweden.
    Bergquist, Filip
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Clin Neurosci, Gothenburg, Sweden;Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Pharmacol, Gothenburg, Sweden.
    Evaluation of a sensor algorithm for motor state rating in Parkinson's disease2019In: Parkinsonism & Related Disorders, ISSN 1353-8020, E-ISSN 1873-5126, Vol. 64, p. 112-117Article in journal (Refereed)
    Abstract [en]

    Introduction: A treatment response objective index (TRIS) was previously developed based on sensor data from pronation-supination tests. This study aimed to examine the performance of TRIS for medication effects in a new population sample with Parkinson's disease (PD) and its usefulness for constructing individual dose-response models.

    Methods: Twenty-five patients with PD performed a series of tasks throughout a levodopa challenge while wearing sensors. TRIS was used to determine motor changes in pronation-supination tests following a single levodopa dose, and was compared to clinical ratings including the Treatment Response Scale (TRS) and six sub-items of the UPDRS part III.

    Results: As expected, correlations between TRIS and clinical ratings were lower in the new population than in the initial study. TRIS was still significantly correlated to TRS (r(s) = 0.23, P < 0.001) with a root mean square error (RMSE) of 1.33. For the patients (n = 17) with a good levodopa response and clear motor fluctuations, a stronger correlation was found (r(s) = 0.38, RMSE = 1.29, P < 0.001). The mean TRIS increased significantly when patients went from the practically defined off to their best on state (P = 0.024). Individual dose-response models could be fitted for more participants when TRIS was used for modelling than when TRS ratings were used.

    Conclusion: The objective sensor index shows promise for constructing individual dose-response models, but further evaluations and retraining of the TRIS algorithm are desirable to improve its performance and to ensure its clinical effectiveness.

  • 5.
    Senek, Marina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    New Approaches for Levodopa Treatment in Parkinson’s Disease2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Parkinson’s disease (PD) is characterized by degeneration of dopaminergic cells, which results in dopamine depletion. Levodopa is the most effective symptomatic treatment, however, disease progression along with the unfavorable pharmacokinetics of levodopa makes the disease increasingly difficult to treat with time.

    This thesis focuses on two new approaches of levodopa treatments, the levodopa/carbidopa microtablets and the levodopa/entacapone/carbidopa intestinal gel, developed for patients with advanced PD.

    To evaluate the microtablet pharmacokinetics and pharmacodynamics in advanced PD patients, a clinical study was conducted. Higher levodopa maximum plasma concentration and systemic exposure was observed in patients compared to healthy volunteers. A high variability, with respect to response and duration of effect, was found, highlighting the importance of individual assessment of motor function to optimize treatment effect. A population pharmacokinetic model for levodopa and carbidopa was developed and the impact of covariates were investigated on the pharmacokinetics. Disease stage and increasing carbidopa dose were found to decrease levodopa apparent clearance. Carbidopa apparent clearance was found to decrease with age. An observational study was conducted, including patients treated with microtablets, in order to evaluate the treatment in clinical practice. A majority reported that the dose dispenser simplified their treatment and improved adherence, while the motor function, with respect to bradykinesia and non-troublesome dyskinesia, was mainly improved or unchanged.

    To investigate the pharmacokinetics and pharmacodynamics of the newly developed levodopa/entacapone/carbidopa intestinal gel treatment, a clinical trial was conducted, where it was compared to the conventional levodopa/carbidopa infusion. The new treatment was found to allow a lower amount of levodopa administration without worsening the treatment effect. An increasing plasma concentration was observed, and a population model was developed for investigation of appropriate dose adjustments. The conclusion was that the continuous maintenance dose could be decreased by approximately 35%, on a population level, compared to the patients’ usual dose on the conventional treatment. An effect from entacapone was identified in all individuals, regardless of catechol-O-methyl transferase genotype (rs4680).

    To conclude, both new treatments are promising alternatives to current strategies and the developed models may in the future be used for model-based treatment optimization.

    List of papers
    1. Levodopa/carbidopa microtablets in Parkinson’s disease: A study of pharmacokinetics and blinded motor assessment
    Open this publication in new window or tab >>Levodopa/carbidopa microtablets in Parkinson’s disease: A study of pharmacokinetics and blinded motor assessment
    Show others...
    2017 (English)In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 73, no 5, p. 563-571Article in journal (Refereed) Published
    National Category
    Neurology
    Identifiers
    urn:nbn:se:uu:diva-320487 (URN)10.1007/s00228-017-2196-4 (DOI)000399175100006 ()28101657 (PubMedID)
    Funder
    VINNOVA
    Available from: 2017-01-18 Created: 2017-04-20 Last updated: 2018-02-28Bibliographically approved
    2. First clinical experience with levodopa/carbidopa microtablets in Parkinson’s disease
    Open this publication in new window or tab >>First clinical experience with levodopa/carbidopa microtablets in Parkinson’s disease
    Show others...
    2017 (English)In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 136, no 6, p. 727-731Article in journal (Refereed) Published
    Abstract [en]

    Background: Levodopa is the most effective symptomatic treatment throughout thecourse of Parkinson’s disease, but as the disease progresses, there may be a need forindividualized, fine-tunedtreatments.

    Aim: To evaluate individualized levodopa/carbidopa dosing using microtablets dispensedwith a dose dispenser, with respect to efficacy and usability as perceived bypatients.

    Methods: Patient records and dose dispenser reports from patients previously or currentlytreated with microtablets and a dose dispenser were reviewed, and a patientquestionnaire concerning effect and usability was sent to patients.

    Results: Eleven patient records, four dose dispenser reports and nine survey responseswere obtained. The treatment effect was considered to be improved by six of ninepatients. One-thirdfound their bradykinesia to be improved, and the non-troublesomedyskinesia was unchanged according to a majority of patients; however, some experiencedthe duration and magnitude of troublesome dyskinesia to be worse. The usabilitywas generally rated as good. The four dose dispenser reports obtained showed97(±5)% total adherence.

    Conclusions: The experienced effect of treatment can, for some patients, be improvedby the use of microtablets, and the dose dispenser was considered user-friendly.Further studies with a larger study population and prospective design are needed toconfirm the results.

    Keywords
    carbidopa, dose dispenser, levodopa, microtablets, Parkinson’s disease, pharmacotherapy
    National Category
    Neurology
    Identifiers
    urn:nbn:se:uu:diva-339874 (URN)10.1111/ane.12756 (DOI)000414488000021 ()
    Available from: 2018-01-23 Created: 2018-01-23 Last updated: 2018-03-21Bibliographically approved
    3. Population pharmacokinetics of levodopa/carbidopa microtablets in healthy subjects and Parkinson’s disease patients
    Open this publication in new window or tab >>Population pharmacokinetics of levodopa/carbidopa microtablets in healthy subjects and Parkinson’s disease patients
    2018 (English)In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 74, no 10, p. 1299-1307Article in journal (Refereed) Published
    Abstract [en]

    Objectives: Low dose, dispersible, levodopa/carbidopa microtablets with an automatic dose dispenser have been developed to facilitate individualized levodopa treatment. The aim of this study was to characterize the pharmacokinetics (PK) of levodopa and carbidopa after microtablet administration, and evaluate the impact of potential covariates.

    Methods: The population PK analysis involved data from 18 healthy subjects and 18 Parkinson's disease patients included in two single-dose, open-label levodopa/carbidopa microtablet studies. The analysis was carried out using non-linear mixed effects modeling. Bodyweight was included on all disposition parameters according to allometric scaling. Potential influence of additional covariates was investigated using graphical evaluation and adjusted adaptive least absolute shrinkage and selection operator.

    Results: Dispositions of levodopa and carbidopa were best described by a two- and one-compartment model respectively. Double-peak profiles were described using two parallel absorption compartments. Levodopa apparent clearance was found to decrease with increasing carbidopa dose (15% lower with 75 compared to 50mg of carbidopa) and disease stage (by 18% for Hoehn and Yahr 1 to 4). Carbidopa apparent clearance was found to decrease with age (28% between the age of 60 and 80years). An external evaluation showed the model to be able to reasonably well predict levodopa concentrations following multiple-dose microtablet administration in healthy subjects.

    Conclusions: The presented models adequately described the PK of levodopa and carbidopa, following microtablet administration. The developed model may in the future be combined with a pharmacokinetic-pharmacodynamic target and used for individualized dose selection, utilizing the flexibility offered by the microtablets.

    National Category
    Neurology
    Identifiers
    urn:nbn:se:uu:diva-343034 (URN)10.1007/s00228-018-2497-2 (DOI)000444387700009 ()29882153 (PubMedID)
    Funder
    VINNOVA
    Available from: 2018-02-25 Created: 2018-02-25 Last updated: 2018-11-13Bibliographically approved
    4. Levodopa-entacapone-carbidopa intestinal gel in Parkinson's disease: A randomized crossover study
    Open this publication in new window or tab >>Levodopa-entacapone-carbidopa intestinal gel in Parkinson's disease: A randomized crossover study
    2017 (English)In: Movement Disorders, ISSN 0885-3185, E-ISSN 1531-8257, Vol. 32, no 2, p. 283-286Article in journal (Refereed) Published
    Abstract [en]

    BackgroundThe addition of oral entacapone to levodopa-carbidopa intestinal gel treatment leads to less conversion of levodopa to 3-O-methyldopa, thereby increasing levodopa plasma concentration. The objective of this study was to compare systemic levodopa exposure of the newly developed levodopa-entacapone-carbidopa intestinal gel after a 20% dose reduction with levodopa exposure after the usual levodopa-carbidopa intestinal gel dose in a randomized crossover trial in advanced Parkinson's disease patients. MethodsIn this 48-hour study, 11 patients treated with levodopa-carbidopa intestinal gel were randomized to a treatment sequence. Blood samples were drawn at prespecified times, and patient motor function was assessed according to the treatment response scale. ResultsSystemic exposure of levodopa did not differ significantly between treatments (ratio, 1.10 [95% confidence interval, 0.951-1.17]). Treatment response scale scores did not significantly differ between treatments (P=0.84). ConclusionsLevodopa-entacapone-carbidopa intestinal gel allowed a lower amount of levodopa administration and was well tolerated. Long-term studies are needed to confirm the results.

    Keywords
    Parkinson's disease, clinical trials, randomized, levodopa infusion, pharmacotherapy
    National Category
    Neurology
    Identifiers
    urn:nbn:se:uu:diva-317042 (URN)10.1002/mds.26855 (DOI)000395645900018 ()27987231 (PubMedID)
    Available from: 2017-03-09 Created: 2017-03-09 Last updated: 2018-02-28Bibliographically approved
    5. Population pharmacokinetics of levodopa intestinal gel in advanced Parkinson's disease patients – effects of simultaneous entacapone infusion and genetic polymorphism
    Open this publication in new window or tab >>Population pharmacokinetics of levodopa intestinal gel in advanced Parkinson's disease patients – effects of simultaneous entacapone infusion and genetic polymorphism
    (English)Manuscript (preprint) (Other academic)
    National Category
    Neurology
    Identifiers
    urn:nbn:se:uu:diva-343035 (URN)
    Available from: 2018-02-25 Created: 2018-02-25 Last updated: 2018-02-28
  • 6.
    Senek, Marina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Aquilonius, Sten-Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Askmark, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Bergquist, Filip
    Constantinescu, Radu
    Ericsson, Anders
    Lycke, Sara
    Medvedev, Alexander
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Systems and Control. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Automatic control.
    Memedi, Mevludin
    Ohlsson, Fredrik
    Spira, Jack
    Westin, Jerker
    Nyholm, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Levodopa/carbidopa microtablets in Parkinson’s disease: A study of pharmacokinetics and blinded motor assessment2017In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 73, no 5, p. 563-571Article in journal (Refereed)
  • 7.
    Senek, Marina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Hellström, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Albo, Jaan
    Vällingby läkarhus, Vällingby, Sweden.
    Svenningsson, Per
    Karolinska institutet, Stockholm, Sweden.
    Nyholm, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    First clinical experience with levodopa/carbidopa microtablets in Parkinson’s disease2017In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 136, no 6, p. 727-731Article in journal (Refereed)
    Abstract [en]

    Background: Levodopa is the most effective symptomatic treatment throughout thecourse of Parkinson’s disease, but as the disease progresses, there may be a need forindividualized, fine-tunedtreatments.

    Aim: To evaluate individualized levodopa/carbidopa dosing using microtablets dispensedwith a dose dispenser, with respect to efficacy and usability as perceived bypatients.

    Methods: Patient records and dose dispenser reports from patients previously or currentlytreated with microtablets and a dose dispenser were reviewed, and a patientquestionnaire concerning effect and usability was sent to patients.

    Results: Eleven patient records, four dose dispenser reports and nine survey responseswere obtained. The treatment effect was considered to be improved by six of ninepatients. One-thirdfound their bradykinesia to be improved, and the non-troublesomedyskinesia was unchanged according to a majority of patients; however, some experiencedthe duration and magnitude of troublesome dyskinesia to be worse. The usabilitywas generally rated as good. The four dose dispenser reports obtained showed97(±5)% total adherence.

    Conclusions: The experienced effect of treatment can, for some patients, be improvedby the use of microtablets, and the dose dispenser was considered user-friendly.Further studies with a larger study population and prospective design are needed toconfirm the results.

  • 8.
    Senek, Marina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Nielsen, Elisabet I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyholm, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Levodopa-entacapone-carbidopa intestinal gel in Parkinson's disease: A randomized crossover study2017In: Movement Disorders, ISSN 0885-3185, E-ISSN 1531-8257, Vol. 32, no 2, p. 283-286Article in journal (Refereed)
    Abstract [en]

    BackgroundThe addition of oral entacapone to levodopa-carbidopa intestinal gel treatment leads to less conversion of levodopa to 3-O-methyldopa, thereby increasing levodopa plasma concentration. The objective of this study was to compare systemic levodopa exposure of the newly developed levodopa-entacapone-carbidopa intestinal gel after a 20% dose reduction with levodopa exposure after the usual levodopa-carbidopa intestinal gel dose in a randomized crossover trial in advanced Parkinson's disease patients. MethodsIn this 48-hour study, 11 patients treated with levodopa-carbidopa intestinal gel were randomized to a treatment sequence. Blood samples were drawn at prespecified times, and patient motor function was assessed according to the treatment response scale. ResultsSystemic exposure of levodopa did not differ significantly between treatments (ratio, 1.10 [95% confidence interval, 0.951-1.17]). Treatment response scale scores did not significantly differ between treatments (P=0.84). ConclusionsLevodopa-entacapone-carbidopa intestinal gel allowed a lower amount of levodopa administration and was well tolerated. Long-term studies are needed to confirm the results.

  • 9.
    Senek, Marina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Nyholm, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Continuous drug delivery in Parkinson's disease2014In: CNS Drugs, ISSN 1172-7047, E-ISSN 1179-1934, Vol. 28, no 1, p. 19-27Article in journal (Refereed)
    Abstract [en]

    Development of motor and non-motor complications during the course of Parkinson’s disease (PD) is a major challenge for therapeutic management. At advanced disease stages, patients frequently fluctuate between PD symptoms–such as bradykinesia–and dyskinesias, in response to fluctuations in drug concentrations. Continuous subcutaneous infusion of the dopamine agonist apomorphine or intestinal infusion of levodopa reduce such fluctuations in both pharmacokinetics and motor function. This is the basis for the concept of continuous drug delivery in PD, and the more theoretical concept of continuous dopaminergic stimulation. These expressions are sometimes used to describe a treatment that is more continuous in its pharmacokinetic profile or that produces more sustained effects, compared with immediate-release levodopa, i.e. not only pump treatments. For example, sustained-release formulations of levodopa or dopamine agonists, transdermal delivery of rotigotine, and addition of catechol-O-methyltransferase inhibitors or monoamine oxidase-B inhibitors have been developed with the aim to provide more continuous drug concentrations, sustained benefits and minimized side effects. Progress has been made, but there are still knowledge gaps regarding how these treatment alternatives can be optimally used. New treatments are currently being developed to provide the continuous drug delivery that is known to successfully alleviate motor and non-motor complications. Hopefully, although not yet proven, these new methods may also prevent or postpone some of the late-stage complications.

  • 10.
    Senek, Marina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyholm, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Nielsen, Elisabet I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Population pharmacokinetics of levodopa/carbidopa microtablets in healthy subjects and Parkinson’s disease patients2018In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 74, no 10, p. 1299-1307Article in journal (Refereed)
    Abstract [en]

    Objectives: Low dose, dispersible, levodopa/carbidopa microtablets with an automatic dose dispenser have been developed to facilitate individualized levodopa treatment. The aim of this study was to characterize the pharmacokinetics (PK) of levodopa and carbidopa after microtablet administration, and evaluate the impact of potential covariates.

    Methods: The population PK analysis involved data from 18 healthy subjects and 18 Parkinson's disease patients included in two single-dose, open-label levodopa/carbidopa microtablet studies. The analysis was carried out using non-linear mixed effects modeling. Bodyweight was included on all disposition parameters according to allometric scaling. Potential influence of additional covariates was investigated using graphical evaluation and adjusted adaptive least absolute shrinkage and selection operator.

    Results: Dispositions of levodopa and carbidopa were best described by a two- and one-compartment model respectively. Double-peak profiles were described using two parallel absorption compartments. Levodopa apparent clearance was found to decrease with increasing carbidopa dose (15% lower with 75 compared to 50mg of carbidopa) and disease stage (by 18% for Hoehn and Yahr 1 to 4). Carbidopa apparent clearance was found to decrease with age (28% between the age of 60 and 80years). An external evaluation showed the model to be able to reasonably well predict levodopa concentrations following multiple-dose microtablet administration in healthy subjects.

    Conclusions: The presented models adequately described the PK of levodopa and carbidopa, following microtablet administration. The developed model may in the future be combined with a pharmacokinetic-pharmacodynamic target and used for individualized dose selection, utilizing the flexibility offered by the microtablets.

  • 11.
    Thomas, Ilias
    et al.
    Dalarna Univ, Dept Microdata Anal, S-79131 Falun, Sweden..
    Alam, Moudud
    Dalarna Univ, Dept Microdata Anal, S-79131 Falun, Sweden..
    Nyholm, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Senek, Marina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Westin, Jerker
    Dalarna Univ, Dept Microdata Anal, S-79131 Falun, Sweden..
    Individual dose-response models for levodopa infusion dose optimization2018In: International Journal of Medical Informatics, ISSN 1386-5056, E-ISSN 1872-8243, Vol. 112, p. 137-142Article in journal (Refereed)
    Abstract [en]

    Background and objective: To achieve optimal effect with continuous infusion treatment in Parkinson's disease (PD), the individual doses (morning dose and continuous infusion rate) are titrated by trained medical personnel. This study describes an algorithmic method to derive optimized dosing suggestions for infusion treatment of PD, by fitting individual dose-response models. The feasibility of the proposed method was investigated using patient chart data.

    Methods: Patient records were collected at Uppsala University hospital which provided dosing information and dose-response evaluations. Mathematical optimization was used to fit individual patient models using the records' information, by minimizing an objective function. The individual models were passed to a dose optimization algorithm, which derived an optimized dosing suggestion for each patient model.

    Results: Using data from a single day's admission the algorithm showed great ability to fit appropriate individual patient models and derive optimized doses. The infusion rate dosing suggestions had 0.88 correlation and 10% absolute mean relative error compared to the optimal doses as determined by the hospital's treating team. The morning dose suggestions were consistency lower that the optimal morning doses, which could be attributed to different dosing strategies and/or lack of on-off evaluations in the morning.

    Conclusion: The proposed method showed promise and could be applied in clinical practice, to provide the hospital personnel with additional information when making dose adjustment decisions.

  • 12.
    Thomas, Ilias
    et al.
    Dalarna Univ, S-79131 Falun, Sweden.
    Westin, Jerker
    Dalarna Univ, S-79131 Falun, Sweden.
    Alam, Moudud
    Dalarna Univ, S-79131 Falun, Sweden.
    Bergquist, Filip
    Gothenburg Univ, S-40530 Gothenburg, Sweden.
    Nyholm, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Senek, Marina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Memedi, Mevludin
    Orebro Univ, S-70281 Orebro, Sweden;Dalarna Univ, S-79131 Falun, Sweden.
    A Treatment-Response Index From Wearable Sensors for Quantifying Parkinson's Disease Motor States2018In: IEEE journal of biomedical and health informatics, ISSN 2168-2194, E-ISSN 2168-2208, Vol. 22, no 5, p. 1341-1349Article in journal (Refereed)
    Abstract [en]

    The goal of this study was to develop an algorithm that automatically quantifies motor states (off, on, dyskinesia) in Parkinson's disease (PD), based on accelerometry during a hand pronation-supination test. Clinician's ratings using the Treatment Response Scale (TRS), ranging from -3 (veryOff) to 0 (On) to +3 (very dyskinetic), were used as target. For that purpose, 19 participants with advanced PD and 22 healthy persons were recruited in a single center open label clinical trial in Uppsala, Sweden. The trial consisted of single levodopa dose experiments for the people with PD (PwP), where participants were asked to perform standardized wrist rotation tests, using each hand, before and at prespecified time points after the dose. The participants used wrist sensors containing a three-dimensional accelerometer and gyroscope. Features to quantify the level, variation, and asymmetry of the sensor signals, three-level discrete wavelet transform features, and approximate entropy measures were extracted from the sensors data. At the time of the tests, the PwP were video recorded. Three movement disorder specialists rated the participants' state on the TRS. A Treatment Response Index from Sensors (TRIS) was constructed to quantify the motor states based on the wrist rotation tests. Different machine learning algorithms were evaluated to map the features derived from the sensor data to the ratings provided by the three specialists. Results from cross validation, both in tenfold and a leave-one-individual out setting, showed good predictive power of a support vector machine model and high correlation to the TRS. Values at the end tails of the TRS were under and over predicted due to the lack of observations at those values but the model managed to accurately capture the dose-effect profiles of the patients. In addition, the TRIS had good test-retest reliability on the baseline levels of the PD participants (Intraclass correlation coefficient of 0.83) and reasonable sensitivity to levodopa treatment (0.33 for the TRIS). For a series of test occasions, the proposed algorithms provided dose-effect time profiles for participants with PD, which could be useful during therapy individualization of people suffering from advanced PD.

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