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Marrinan, S. L., Otiker, T., Vasist, L. S., Gibson, R. A., Sarai, B. K., Barton, M. E., . . . Burn, D. J. (2018). A randomized, double-blind, placebo-controlled trial of camicinal in Parkinson's disease.. Movement Disorders, 33(2), 329-332
Open this publication in new window or tab >>A randomized, double-blind, placebo-controlled trial of camicinal in Parkinson's disease.
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2018 (English)In: Movement Disorders, ISSN 0885-3185, E-ISSN 1531-8257, Vol. 33, no 2, p. 329-332Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Delayed gastric emptying may impair l-dopa absorption, contributing to motor fluctuations. We evaluated the effect of camicinal (GSK962040), a gastroprokinetic, on the absorption of l-dopa and symptoms of PD.

METHODS: Phase II, double-blind, placebo-controlled trial. Participants were randomized to receive camicinal 50 mg once-daily (n = 38) or placebo (n = 20) for 7 to 9 days.

RESULTS: l-dopa exposure was similar with coadministration of camicinal compared to placebo. Median time to maximum l-dopa concentration was reduced, indicating more rapid absorption of l-dopa. Camicinal resulted in significant reduction in OFF time (-2.31 hours; 95% confidence interval: -3.71, -0.90), significant increase in ON time (+1.88 hours; 95% confidence interval: 0.28, 3.48) per day, and significant decrease in mean total MDS-UPDRS score (-12.5; 95% confidence interval: -19.67, -5.29). Camicinal treatment was generally well tolerated.

CONCLUSIONS: PD symptom improvement with camicinal occurred in parallel with more rapid absorption of l-dopa. This study provides evidence of an improvement of the motor response to l-dopa in people with PD treated with camicinal 50 mg once-daily compared with placebo, which will require further evaluation.

Keywords
Clinical trials Randomized controlled (CONSORT agreement), Parkinson's disease/parkinsonism
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-343107 (URN)10.1002/mds.27259 (DOI)000424815100022 ()29278279 (PubMedID)
Funder
GlaxoSmithKline (GSK)
Available from: 2018-02-25 Created: 2018-02-25 Last updated: 2018-03-26Bibliographically approved
Thomas, I., Alam, M., Nyholm, D., Senek, M. & Westin, J. (2018). Individual dose-response models for levodopa infusion dose optimization. International Journal of Medical Informatics, 112, 137-142
Open this publication in new window or tab >>Individual dose-response models for levodopa infusion dose optimization
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2018 (English)In: International Journal of Medical Informatics, ISSN 1386-5056, E-ISSN 1872-8243, Vol. 112, p. 137-142Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
ELSEVIER IRELAND LTD, 2018
Keywords
Levodopa infusion, Algorithmic dosing suggestions, Patient-specific models, Parkinson's disease
National Category
Other Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-350278 (URN)10.1016/j.ijmedinf.2018.01.018 (DOI)000426130900018 ()29500011 (PubMedID)
Funder
Knowledge FoundationVINNOVA
Available from: 2018-05-14 Created: 2018-05-14 Last updated: 2018-05-14Bibliographically approved
Johansson, D., Ericsson, A., Johansson, A., Medvedev, A., Nyholm, D., Ohlsson, F., . . . Bergquist, F. (2018). Individualization of levodopa treatment using a microtablet dispenser and ambulatory accelerometry. CNS Neuroscience & Therapeutics, 24(5), 439-447
Open this publication in new window or tab >>Individualization of levodopa treatment using a microtablet dispenser and ambulatory accelerometry
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2018 (English)In: CNS Neuroscience & Therapeutics, ISSN 1755-5930, E-ISSN 1755-5949, Vol. 24, no 5, p. 439-447Article in journal (Refereed) Published
National Category
Neurology Control Engineering
Identifiers
urn:nbn:se:uu:diva-354110 (URN)10.1111/cns.12807 (DOI)000430058800008 ()29652438 (PubMedID)
Available from: 2018-01-25 Created: 2018-06-19 Last updated: 2018-06-20Bibliographically approved
Jonasson, M., Appel, L., Danfors, T., Nyholm, D., Askmark, H., Frick, A., . . . Lubberink, M. (2017). Development of a clinically feasible [11C]PE2I PET method for differential diagnosis of parkinsonism using reduced scan duration and automated reference region extraction.. American Journal of Nuclear Medicine and Molecular Imaging, 7(6), 263-274
Open this publication in new window or tab >>Development of a clinically feasible [11C]PE2I PET method for differential diagnosis of parkinsonism using reduced scan duration and automated reference region extraction.
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2017 (English)In: American Journal of Nuclear Medicine and Molecular Imaging, ISSN 2160-8407, Vol. 7, no 6, p. 263-274Article in journal (Refereed) Published
Abstract [en]

[11C]PE2I is a highly selective dopamine transporter PET ligand. Parametric images based on dynamic [11C]PE2I scans, showing dopamine transporter availability (BPND) and relative cerebral blood flow (R1), can be used in differential diagnosis of parkinsonism. This work aimed to investigate a shortened scan duration and automated generation of parametric images which are two prerequisites for routine clinical application. Twelve subjects with parkinsonism and seventeen healthy controls underwent 80 min dynamic [11C]PE2I PET scans. BPND and R1 images were generated using cerebellum reference region defined on a co-registered MRI, as well as a supervised cluster analysis (SVCA)-based reference. Initial 20, 30 and 40 min of the scans were extracted and images of standardized uptake value ratio (SUVR) and R1 were computed using MRI- and SVCA-based reference. Correlation was high between striatal 80 min MRI-based BPND and 40 min SVCA-based SUVR-1 (R2=0.95). High correlation was also found between R1 values in striatal and limbic regions (R2≥0.91) whereas correlation was moderate for cortical regions (R2=0.71). The results indicate that dynamic [11C]PE2I scans can be restricted to 40 min and that SVCA can be used for automatic extraction of a reference region. These outcomes will support routine applications of [11C]PE2I PET in clinical settings.

Keywords
PET, [11C]PE2I, parametric images, parkinsonism, supervised clustering
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-340790 (URN)000419593300003 ()29348981 (PubMedID)
Funder
Swedish Research CouncilSwedish Society for Medical Research (SSMF)
Available from: 2018-02-02 Created: 2018-02-02 Last updated: 2018-02-21Bibliographically approved
Aquilonius, S.-M. & Nyholm, D. (2017). Development of new levodopa treatment strategies in Parkinson’s disease – from bedside to bench to bedside. Upsala Journal of Medical Sciences, 122(2), 71-77
Open this publication in new window or tab >>Development of new levodopa treatment strategies in Parkinson’s disease – from bedside to bench to bedside
2017 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 2, p. 71-77Article, review/survey (Refereed) Published
Abstract [en]

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'.

Keywords
Carbidopa; drug development; intestinal gel; levodopa; microtablets; Parkinson's disease
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-320484 (URN)10.1080/03009734.207.1285374 (DOI)000401756500001 ()28276779 (PubMedID)
Available from: 2017-04-20 Created: 2017-04-20 Last updated: 2017-10-17Bibliographically approved
Sadikov, A., Groznik, V., Mozina, M., Zabkar, J., Nyholm, D., Memedi, M., . . . Georgiev, D. (2017). Feasibility of spirography features for objective assessment of motor function in Parkinson's disease. Paper presented at 15th Conference on Artificial Intelligence in Medicine (AIME), JUN 17-20, 2015, Univ Pavia, Pavia, ITALY. Artificial Intelligence in Medicine, 81(SI), 54-62
Open this publication in new window or tab >>Feasibility of spirography features for objective assessment of motor function in Parkinson's disease
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2017 (English)In: Artificial Intelligence in Medicine, ISSN 0933-3657, E-ISSN 1873-2860, Vol. 81, no SI, p. 54-62Article in journal (Refereed) Published
Abstract [en]

Objective: Parkinson's disease (PD) is currently incurable, however proper treatment can ease the symptoms and significantly improve the quality of life of patients. Since PD is a chronic disease, its efficient monitoring and management is very important. The objective of this paper was to investigate the feasibility of using the features and methodology of a spirography application, originally designed to detect early Parkinson's disease (PD) motoric symptoms, for automatically assessing motor symptoms of advanced PD patients experiencing motor fluctuations. More specifically, the aim was to objectively assess motor symptoms related to bradykinesias (slowness of movements occurring as a result of under-medication) and dyskinesias (involuntary movements occurring as a result of over-medication).

Materials and methods: This work combined spirography data and clinical assessments from a longitudinal clinical study in Sweden with the features and pre-processing methodology of a Slovenian spirography application. The study involved 65 advanced PD patients and over 30,000 spiral-drawing measurements over the course of three years. Machine learning methods were used to learn to predict the "cause" (bradykinesia or dyskinesia) of upper limb motor dysfunctions as assessed by a clinician who observed animated spirals in a web interface. The classification model was also tested for comprehensibility. For this purpose a visualisation technique was used to present visual clues to clinicians as to which parts of the spiral drawing (or its animation) are important for the given classification.

Results: Using the machine learning methods with feature descriptions and pre-processing from the Slovenian application resulted in 86% classification accuracy and over 0.90 AUC. The clinicians also rated the computer's visual explanations of its classifications as at least meaningful if not necessarily helpful in over 90% of the cases.

Conclusions: The relatively high classification accuracy and AUC demonstrates the usefulness of this approach for objective monitoring of PD patients. The positive evaluation of computer's explanations suggests the potential use of this methodology in a decision support setting.

Keywords
Parkinson's disease, Movement disorder, Spirography, Spirography features, Objective monitoring, Visualisation
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-340159 (URN)10.1016/j.artmed.2017.03.011 (DOI)000413608900006 ()28416144 (PubMedID)
Conference
15th Conference on Artificial Intelligence in Medicine (AIME), JUN 17-20, 2015, Univ Pavia, Pavia, ITALY
Funder
VINNOVA
Available from: 2018-02-01 Created: 2018-02-01 Last updated: 2018-02-01Bibliographically approved
Senek, M., Hellström, M., Albo, J., Svenningsson, P. & Nyholm, D. (2017). First clinical experience with levodopa/carbidopa microtablets in Parkinson’s disease. Acta Neurologica Scandinavica, 136(6), 727-731
Open this publication in new window or tab >>First clinical experience with levodopa/carbidopa microtablets in Parkinson’s disease
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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
Willows, T., Dizdar, N., Nyholm, D., Widner, H., Grenholm, P., Schmiauke, U., . . . Kjellander, S. (2017). Initiation of Levodopa-Carbidopa Intestinal Gel Infusion Using Telemedicine (Video Communication System) Facilitates Efficient and Well-Accepted Home Titration in Patients with Advanced Parkinson's Disease. Journal of Parkinson's Disease, 7(4), 719-728
Open this publication in new window or tab >>Initiation of Levodopa-Carbidopa Intestinal Gel Infusion Using Telemedicine (Video Communication System) Facilitates Efficient and Well-Accepted Home Titration in Patients with Advanced Parkinson's Disease
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2017 (English)In: Journal of Parkinson's Disease, ISSN 1877-7171, E-ISSN 1877-718X, Vol. 7, no 4, p. 719-728Article in journal (Refereed) Published
Abstract [en]

Background: Levodopa-carbidopa intestinal gel (LCIG; Duodopa r) 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.

Keywords
Advanced Parkinson's disease, levodopa-carbidopa intestinal gel, LCIG, duodenal levodopa-carbidopa infusion, Duodopa, telemedicine, video communication system, home titration, routine patient care, healthcare resource utilization
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-343148 (URN)10.3233/JPD-161048 (DOI)000416092100018 ()28984615 (PubMedID)
Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2018-02-26Bibliographically approved
Virhammar, J. & Nyholm, D. (2017). Levodopa-carbidopa enteral suspension in advanced Parkinson's disease: clinical evidence and experience. Therapeutic advances in neurological disorders, 10(3), 171-187
Open this publication in new window or tab >>Levodopa-carbidopa enteral suspension in advanced Parkinson's disease: clinical evidence and experience
2017 (English)In: Therapeutic advances in neurological disorders, ISSN 1756-2856, Vol. 10, no 3, p. 171-187Article, review/survey (Refereed) Published
Abstract [en]

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.

National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-320486 (URN)10.1177/1756285616681280 (DOI)000396212700003 ()28344656 (PubMedID)
Available from: 2017-04-20 Created: 2017-04-20 Last updated: 2017-05-04Bibliographically approved
Senek, M., Aquilonius, S.-M., Askmark, H., Bergquist, F., Constantinescu, R., Ericsson, A., . . . Nyholm, D. (2017). Levodopa/carbidopa microtablets in Parkinson’s disease: A study of pharmacokinetics and blinded motor assessment. European Journal of Clinical Pharmacology, 73(5), 563-571
Open this publication in new window or tab >>Levodopa/carbidopa microtablets in Parkinson’s disease: A study of pharmacokinetics and blinded motor assessment
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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
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-9776-7715

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