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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, 71-77 p.Article, 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'.

Keyword
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
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, 171-187 p.Article, 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, 563-571 p.Article 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: 2017-05-17Bibliographically approved
Senek, M., Nielsen, E. I. & Nyholm, D. (2017). Levodopa-entacapone-carbidopa intestinal gel in Parkinson's disease: A randomized crossover study. Movement Disorders, 32(2), 283-286.
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, 283-286 p.Article 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.

Keyword
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: 2017-04-25Bibliographically approved
Wirdefeldt, K., Odin, P. & Nyholm, D. (2016). Authors' Reply to Lambarth: "Levodopa-Carbidopa Intestinal Gel in Patients with Parkinson's Disease: A Systematic Review" [Letter to the editor]. CNS Drugs, 30(10), 1009-1010.
Open this publication in new window or tab >>Authors' Reply to Lambarth: "Levodopa-Carbidopa Intestinal Gel in Patients with Parkinson's Disease: A Systematic Review"
2016 (English)In: CNS Drugs, ISSN 1172-7047, E-ISSN 1179-1934, Vol. 30, no 10, 1009-1010 p.Article in journal, Letter (Refereed) Published
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-309830 (URN)10.1007/s40263-016-0379-7 (DOI)000384580200009 ()27541606 (PubMedID)
Available from: 2016-12-08 Created: 2016-12-07 Last updated: 2017-11-29Bibliographically approved
Wirdefeldt, K., Odin, P. & Nyholm, D. (2016). Levodopa–Carbidopa Intestinal Gel in Patients with Parkinson’s Disease: A Systematic Review. CNS Drugs, 30(5), 381-404.
Open this publication in new window or tab >>Levodopa–Carbidopa Intestinal Gel in Patients with Parkinson’s Disease: A Systematic Review
2016 (English)In: CNS Drugs, ISSN 1172-7047, E-ISSN 1179-1934, Vol. 30, no 5, 381-404 p.Article, review/survey (Refereed) Published
Abstract [en]

Background Levodopa-carbidopa intestinal gel (LCIG) is available in several countries for the treatment of advanced levodopa-responsive Parkinson's disease (PD) with severe motor fluctuations and dyskinesia when other treatments have not given satisfactory results. Objective Our objective was to summarize the present evidence base for LCIG therapy through a systematic review of the literature. Methods Studies were identified from the PubMed and EMBASE databases up to 12 March 2016 using the following search terms: Parkinson disease, duodopa, levodopa/carbidopa intestinal gel, levodopa-carbidopa intestinal gel, LCIG, l-dopa infusion, levodopa infusion, duodenal l-dopa infusion, and duodenal levodopa infusion. Data extraction focused on whether LCIG therapy improves motor and non-motor outcomes as well as quality of life in PD patients compared with conventional therapy, apomorphine infusion, or deep brain stimulation. Randomized controlled trials (RCTs) and observational studies, with or without a control group, that included more than ten patients were included. The search was limited to peer-reviewed articles published in full in the English language and involving humans. Results Infusion of LCIG reduced "off'' time, increased "on'' time without increasing troublesome dyskinesias, and improved quality of life in three RCTs (one double-blind). Open-label follow-ups confirm these findings. The data evaluating long-term efficacy and safety are still limited. Conclusions The quality of evidence that LCIG is effective in reducing fluctuating motor symptoms and improving quality of life is moderate. Quality of evidence for reduction of non-motor symptoms is very low. Safety issues mainly relate to the intestinal infusion system. LCIG might be a useful treatment option in PD patients with severe motor fluctuations.

National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-294450 (URN)10.1007/s40263-016-0336-5 (DOI)000376414100003 ()27138916 (PubMedID)
Available from: 2016-05-21 Created: 2016-05-21 Last updated: 2017-11-30Bibliographically approved
Pålhagen, S. E., Sydow, O., Johansson, A., Nyholm, D., Holmberg, B., Widner, H., . . . Marshall, T. S. (2016). Levodopa-carbidopa intestinal gel (LCIG) treatment in routine care of patients with advanced Parkinson's disease: An open-label prospective observational study of effectiveness, tolerability and healthcare costs. Parkinsonism & Related Disorders, 29, 17-23.
Open this publication in new window or tab >>Levodopa-carbidopa intestinal gel (LCIG) treatment in routine care of patients with advanced Parkinson's disease: An open-label prospective observational study of effectiveness, tolerability and healthcare costs
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2016 (English)In: Parkinsonism & Related Disorders, ISSN 1353-8020, E-ISSN 1873-5126, Vol. 29, 17-23 p.Article in journal (Refereed) Published
Abstract [en]

Background: Continuous infusion of levodopa-carbidopa intestinal gel (LCIG) can effectively manage motor and non-motor complications in advanced Parkinson's disease (PD). Healthcare costs, quality of life (QoL), effectiveness, and tolerability were assessed in routine care treatment with LCIG. Methods: The seventy-seven patients enrolled in this prospective, open-label, 3-year study in routine medical care were LCIG-naive (N = 37), or had previous LCIG treatment for <2 (N = 22), or >= 2 (N = 18) years. Healthcare costs were collected monthly. PD symptoms and QoL were assessed with the Unified Parkinson's Disease Rating Scale (UPDRS), 39-item Parkinson's Disease Questionnaire (PDQ-39), and EuroQoL 5-Dimension Visual Analog Scale (EQ-5D VAS); LCIG dose, safety, and tolerability were monitored. Results: Mean monthly costs per patient ( 8226 5952) were similar across cohorts, remained steady during 3-year follow-up, and increased with PD severity and QoL impairment. In LCIG-naive patients, significant improvements compared to baseline were observed on the UPDRS total score and PDQ-39 summary index score through 18 months (n = 24; UPDRS, p = 0.033; PDQ-39, p = 0.049). Symptom control was maintained during 3-year follow-up in LCIG-experienced cohorts. Small changes in mean daily LCIG dose were observed. Adverse events were common and generally related to the device, procedure, levodopa, or laboratory evaluations. Conclusions: Costs in LCIG-treated patients were stable over 3 years. LCIG treatment led to significant improvements in motor function and QoL over 18 months in LCIG-naive patients and no worsening was observed in LCIG-experienced patients over 3 years despite natural PD progression over time. The longterm safety was consistent with the established LCIG profile.

Keyword
Parkinson's disease; Levodopa; Infusion; LCIG; Cost
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-300787 (URN)10.1016/j.parkreldis.2016.06.002 (DOI)000381955700004 ()27318707 (PubMedID)
Available from: 2016-08-13 Created: 2016-08-13 Last updated: 2017-11-28Bibliographically approved
van Laar, T., Nyholm, D. & Nyman, R. (2016). Transcutaneous port for levodopa/carbidopa intestinal gel administration in Parkinson's disease. Acta Neurologica Scandinavica, 133(3), 208-215.
Open this publication in new window or tab >>Transcutaneous port for levodopa/carbidopa intestinal gel administration in Parkinson's disease
2016 (English)In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 133, no 3, 208-215 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To evaluate the safety and tolerability of the T-Port(®) for intestinal infusion of levodopa/carbidopa gel in patients with advanced Parkinson's disease (PD).

METHODS: This prospective study was carried out in 24 patients with PD (15 males, mean age 61.8 years, mean duration PD 18.7 years). All adverse device effects were evaluated at 2 weeks, 3 months and 6 months and until explantation or death.

RESULTS: Post-operative complications were similar to endoscopic gastrojejunostomy placement (four peritoneal irritation, one pocket pain). Eight patients with prior experience with the endoscopic gastrojejunostomy preferred the T-Port. The total device experience was 83.6 years, and the average survival time was 3.6 (range 1.1-5.2) years. Six T-Ports were still in use, and two patients had died due to non-device-related reasons. Sixteen T-Ports had been explanted due to 15 stoma reactions (14 inflammations and one infection) and one tilting of the T-Port. The T-Ports were replaced with endoscopic gastrojejunostomy system as replacements with T-Ports were not part of the study. Only two device malfunctions occurred (one catheter breakage at 3 year post-implant and one T-Port leakage of levodopa/carbidopa gel). No tube kinking, dislocation or blockage occurred. The number of adverse device effects proved to be significantly lower as compared to the endoscopic gastrojejunostomy literature data.

CONCLUSIONS: The T-Port is safe and well tolerated, and the low number of tube problems is a potential advantage compared with the endoscopic gastrojejunostomy system. Proper cleaning and local treatment of the stoma site around the T-Port are essential to prolong its longevity.

Keyword
clinical trial; levodopa/carbidopa infusion; Parkinson's disease; percutaneous endoscopic gastrojejunostomy; transcutaneous port
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-261204 (URN)10.1111/ane.12464 (DOI)000371628100006 ()26213103 (PubMedID)
Funder
Swedish Research CouncilVINNOVA
Available from: 2015-08-31 Created: 2015-08-31 Last updated: 2017-12-04Bibliographically approved
Sousa, J. M., Appel, L., Papadimitriou, S., Nyholm, D., Sörensen, J., Danfors, T., . . . Lubberink, M. (2016). Validation of Zero-Echo Time PET-MR against stand-alone PET using dynamic dopamine transporter imaging. Paper presented at Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 15-19, 2016, Barcelona, SPAIN. European Journal of Nuclear Medicine and Molecular Imaging, 43, S79-S79.
Open this publication in new window or tab >>Validation of Zero-Echo Time PET-MR against stand-alone PET using dynamic dopamine transporter imaging
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2016 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, S79-S79 p.Article in journal, Meeting abstract (Refereed) Published
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-316224 (URN)000391801600183 ()
Conference
Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 15-19, 2016, Barcelona, SPAIN
Available from: 2017-02-27 Created: 2017-02-27 Last updated: 2017-11-29Bibliographically approved
Rystedt, A., Zetterberg, L., Burman, J., Nyholm, D. & Johansson, A. (2015). A Comparison of Botox 100 U/mL and Dysport 100 U/mL Using Dose Conversion Ratio 1: 3 and 1: 1.7 in the Treatment of Cervical Dystonia: A Double-Blind, Randomized, Crossover Trial. Clinical neuropharmacology, 38(5), 170-176.
Open this publication in new window or tab >>A Comparison of Botox 100 U/mL and Dysport 100 U/mL Using Dose Conversion Ratio 1: 3 and 1: 1.7 in the Treatment of Cervical Dystonia: A Double-Blind, Randomized, Crossover Trial
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2015 (English)In: Clinical neuropharmacology, ISSN 0362-5664, E-ISSN 1537-162X, Vol. 38, no 5, 170-176 p.Article in journal (Refereed) Published
Abstract [en]

Objectives: Intramuscular injections of botulinum toxin (BTX) are used as symptomatic treatment for cervical dystonia. Botox and Dysport are commercial products containing BTX; however, dosage and concentration of the prepared solution vary considerably among studies. The concentration of BTX in the prepared solution affects clinical outcome. This double-blind, randomized crossover trial compares Botox and Dysport in 2 different dose conversion ratios (1:3 and 1:1.7) when diluted to the same concentration (100 U/mL).

Methods: Forty-six patients with cervical dystonia received 3 different treatments, Botox in 2 different doses and Dysport as control treatment. The efficacy was evaluated 4 and 12 weeks after treatment using 5 instruments, including Toronto Western Spasmodic Torticollis Rating Scale.

Results and Conclusion: The primary outcome was the estimated median Toronto Western Spasmodic Torticollis Rating Scale total score, which was 1.96 points higher for Botox (1:3) compared with Dysport at week 4, but the difference was not statistically significant (confidence interval, -0.88–4.61; P = 0.0799). No significant differences were seen between Botox (1:1.7) and Dysport. At week 12, a statistically significant difference in effect between Botox (1:3) and Dysport was observed, suggesting a shorter duration of effect for Botox when this ratio (low dose) was used. Furthermore, the patients' assessments showed that the ratio 1:3 resulted in suboptimal efficacy of Botox. These secondary outcome observations indicate that the dose conversion ratio between Dysport 100 U/mL and Botox 100 U/mL may be lower than 1:3, but this must be further validated in a larger patient material.

National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:uu:diva-264356 (URN)10.1097/WNF.0000000000000101 (DOI)000362107900002 ()26366966 (PubMedID)
Available from: 2015-10-09 Created: 2015-10-09 Last updated: 2017-12-01Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0001-9776-7715

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