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Johansson, Anders
Publications (10 of 12) Show all publications
Nyholm, D., Odin, P., Johansson, A., Chatamra, K., Locke, C., Dutta, S. & Othman, A. A. (2013). Pharmacokinetics of Levodopa, Carbidopa, and 3-O-Methyldopa Following 16-hour Jejunal Infusion of Levodopa-Carbidopa Intestinal Gel in Advanced Parkinson's Disease Patients. AAPS Journal, 15(2), 316-323
Open this publication in new window or tab >>Pharmacokinetics of Levodopa, Carbidopa, and 3-O-Methyldopa Following 16-hour Jejunal Infusion of Levodopa-Carbidopa Intestinal Gel in Advanced Parkinson's Disease Patients
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2013 (English)In: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 15, no 2, p. 316-323Article in journal (Refereed) Published
Abstract [en]

Motor complications of Parkinson's disease (PD) are a consequence of pulsatile dopaminergic stimulation from standard oral levodopa therapy. Levodopa-carbidopa intestinal gel (LCIG) is infused continuously via an intrajejunal percutaneous gastrostomy tube. This was the first study designed to characterize the full pharmacokinetic profiles of levodopa, carbidopa, and levodopa metabolite, 3-O-methyldopa (3-OMD) with 16-h LCIG infusion. Nineteen advanced PD patients (mean age, 65 years) who were on LCIG therapy for ≥30 days were enrolled. Patients received their individualized LCIG infusion doses, and serial pharmacokinetic samples were collected. Eighteen patients completed the study; 19 were assessed for safety. Mean (SD) total levodopa and carbidopa doses were 1,580 (403) and 395 (101) mg, respectively. Mean (SD) C (avg) (μg/mL) were 2.9 (0.84) for levodopa, 17.1 (4.99) for 3-OMD, and 0.22 (0.08) for carbidopa. The degree of fluctuation [defined as (C (max) - C (min))/C (avg)] in levodopa, 3-OMD, and carbidopa plasma concentrations was very low (0.52, 0.21, and 0.96, respectively) during hours 2-16 of infusion. Accordingly, the within-subject coefficients of variation in levodopa, 3-OMD, and carbidopa concentrations were low (13%, 6%, and 19%, respectively). Three patients (16%) reported ≥1 treatment-emergent adverse event; none were considered severe. Continuous intrajejunal LCIG infusion maintained stable plasma levodopa levels over 16 h. Consistent exposure has been shown to reduce motor and nonmotor complications associated with oral medications. LCIG was well tolerated, consistent with previous reports.

National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:uu:diva-188369 (URN)10.1208/s12248-012-9439-1 (DOI)000317136100003 ()23229334 (PubMedID)
Available from: 2012-12-17 Created: 2012-12-17 Last updated: 2017-12-06Bibliographically approved
Nyholm, D., Johansson, A., Aquilonius, S.-M., Hellquist, E., Lennernäs, H. & Askmark, H. (2012). Complexity of Motor Response to Different Doses of Duodenal Levodopa Infusion in Parkinson Disease. Clinical neuropharmacology, 35(1), 6-14
Open this publication in new window or tab >>Complexity of Motor Response to Different Doses of Duodenal Levodopa Infusion in Parkinson Disease
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2012 (English)In: Clinical neuropharmacology, ISSN 0362-5664, E-ISSN 1537-162X, Vol. 35, no 1, p. 6-14Article, review/survey (Refereed) Published
Abstract [en]

OBJECTIVE:

The aim was to elaborately describe individual pharmacokinetic-pharmacodynamic profiles in patients with difficult-to-treat dyskinesias treated with levodopa/carbidopa intestinal gel infusion.

METHODS:

A nonrandomized, partly blinded, investigator-initiated trial was conducted in 5 patients with idiopathic Parkinson disease who were difficult to keep in "on" state without dyskinesia. Levodopa/carbidopa intestinal gel (Duodopa) doses of 80% to 120% of individually and clinically optimized dosage were infused during five 4-hour periods. Pharmacokinetic profiling, blinded assessment of video recordings, and objective movement analysis were applied every 20 to 30 minutes.

RESULTS:

Individual correlations between plasma levodopa concentrations and corresponding motor scores 20 to 30 minutes after the sampling time were significant in all patients (P < 0.05 and P < 0.001). Motor scores were generally stable during the 4-hour periods. The objective test revealed that motor performance was faster the more dyskinetic the patients were. Mean individual Treatment Response Scale scores were positive in 24 of the 25 steady-state periods. Dystonia was always combined with choreic dyskinesias.

CONCLUSIONS:

Motor response from different doses of levodopa/carbidopa intestinal gel is in a broad sense predictable even in dyskinetic patients although major interindividual differences in dose requirement, plasma levels, and motor response are found. That motor performance was faster the more dyskinetic the patients were implies that motor performance may be better with moderate dyskinesia than with mild dyskinesia. This may explain why patients with persistent dyskinesias choose to keep their doses above the dyskinesia threshold. There is no ideal therapeutic window in such patients, but levodopa infusion offers stable motor response.

National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:uu:diva-164281 (URN)10.1097/WNF.0b013e31823b1ffd (DOI)000299307800002 ()22094648 (PubMedID)
Available from: 2011-12-19 Created: 2011-12-19 Last updated: 2017-12-08Bibliographically approved
Johansson, A. & Nyholm, D. (2012). Continuous delivery of energy or L-dopa: Identifying advantages and limitations of DBS and levodopa-carbidopa intestinal gel in ansence of head-to-head comparisons. Basal Ganglia, 2(4), 221-226
Open this publication in new window or tab >>Continuous delivery of energy or L-dopa: Identifying advantages and limitations of DBS and levodopa-carbidopa intestinal gel in ansence of head-to-head comparisons
2012 (English)In: Basal Ganglia, Vol. 2, no 4, p. 221-226Article in journal (Refereed) Published
Abstract [en]

Deep brain stimulation (DBS) and levodopa–carbidopa intestinal gel (LCIG) are invasive, efficacious treatments for advanced Parkinson’s disease, but so far head-to-head comparisons are scarce. Although their indications and improvements in motor outcome and quality of life may be broadly similar, these treatment modalities have different modes of action and side effect profiles. This article summarizes a presentation at the 2nd International Conference on Knowledge Gaps in Parkinson’s Disease and other Movement Disorders in Feburary 2012. An overview of the existing evidence for efficacy and adverse events of LCIG and DBS in short- and long-term is provided. Examples of factors at present affecting choice of treatment are given. The obvious knowledge gap is the need to better identify the appropriate time and place to operate patients with Parkinson’s disease. There are major difficulties facing us when trying to resolve this issue. We argue for a registry of patients exposed to these very efficacious, but expensive and potentially harmful, symptomatic treatments.

National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:uu:diva-187295 (URN)10.1016/j.baga.2012.05.002 (DOI)
Available from: 2012-12-04 Created: 2012-12-04 Last updated: 2012-12-04Bibliographically approved
Pålhagen, S. E., Dizdar, N., Hauge, T., Holmberg, B., Jansson, R., Linder, J., . . . Johansson, A. (2012). Interim analysis of long-term intraduodenal levodopa infusion in advanced Parkinson disease. Acta Neurologica Scandinavica, 126(6), e29-e33
Open this publication in new window or tab >>Interim analysis of long-term intraduodenal levodopa infusion in advanced Parkinson disease
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2012 (English)In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 126, no 6, p. e29-e33Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: This interim 12-month analysis is a part of an open-label, observational, prospective study on health outcomes and cost impact of levodopa/carbidopa intestinal gel (LCIG, Duodopa) in Parkinson disease (PD). The specific aim was to investigate clinical and health-related quality of life (HRQoL) effects in routine care.

METHODS: Unified PD rating scale (UPDRS) was the primary efficacy measurement. PD QoL questionnaire 39 (PDQ-39) assessed HRQoL. Subjects were assessed at baseline, ≥3 months after surgery, and then every 3 months.

RESULTS: Twenty-seven treatment-naïve subjects when started with LCIG showed a decrease in UPDRS score that was statistically significant throughout the year: UPDRS total score (mean ± SD), baseline = 52.1 ± 16.1, N = 27, month 0 (first visit; at least 3 months after permanent LCIG) = 43.1 ± 16.7, N = 27, P = 0.003; month 12 = 42.5 ± 22.6, n = 25, P = 0.017. PDQ-39 results also showed a tendency for improvement: PDQ-39 (mean ± SD), baseline = 33.6 ± 10.8, N = 27, month 0 = 27.1 ± 11.8, N = 27, P = 0.001; 12 months = 28.8 ± 12.8, n = 23, P = 0.126.

CONCLUSIONS: LCIG provides functional improvement beginning at first visit that is sustained for 12 months.

National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:uu:diva-185433 (URN)10.1111/j.1600-0404.2012.01689.x (DOI)000310545400001 ()22690905 (PubMedID)
Available from: 2012-11-23 Created: 2012-11-23 Last updated: 2017-12-07Bibliographically approved
Nyholm, D., Johansson, A., Lennernäs, H. & Askmark, H. (2012). Levodopa infusion combined with entacapone or tolcapone in Parkinson disease: a pilot trial. European Journal of Neurology, 19(6), 820-826
Open this publication in new window or tab >>Levodopa infusion combined with entacapone or tolcapone in Parkinson disease: a pilot trial
2012 (English)In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 19, no 6, p. 820-826Article in journal (Refereed) Published
Abstract [en]

Background and purpose: 

Catechol-O-methyltransferase inhibitors may be used to decrease levodopa requirement. The objective was to investigate whether the levodopa/carbidopa intestinal gel infusion dose can be reduced by 20% without worsening of motor fluctuations and levodopa concentration stability when oral catechol-O-methyltransferase inhibitors are added.

Methods: 

A short-term, randomized, partly blinded, crossover, investigator-initiated clinical trial was performed, with levodopa/carbidopa intestinal gel combined with oral entacapone and tolcapone on two different days in 10 patients. The primary outcome measure was difference in coefficient of variation of levodopa in plasma between levodopa/carbidopa, levodopa/carbidopa/entacapone, and levodopa/carbidopa/tolcapone. The secondary outcome measures other pharmacokinetic variables, patient-reported outcome, and blinded analysis of motor performance.

Results:

Variation of plasma levodopa concentrations did not differ significantly between the treatments. The treatments did not differ regarding motor performance. Levodopa concentrations were significantly higher using tolcapone. Concentrations of the metabolite 3-O-methyldopa decreased gradually during catechol-O-methyltransferase inhibition.

Conclusions: 

According to this small, short-term pilot study, oral catechol-O-methyltransferase inhibitors administered in 5-h intervals may be useful in cases where levodopa/carbidopa intestinal gel dose reduction is wanted. Stability of plasma levodopa levels is not significantly altered, and off-time is not increased when decreasing the levodopa/carbidopa intestinal gel dose by 20%. Rather, the dose should probably be decreased more than 20%, especially under tolcapone co-treatment, to avoid increased dyskinesias with time.

National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:uu:diva-164279 (URN)10.1111/j.1468-1331.2011.03614.x (DOI)000303911600010 ()22136163 (PubMedID)
Available from: 2011-12-19 Created: 2011-12-19 Last updated: 2017-12-08Bibliographically approved
Nyholm, D., Lennernäs, H., Johansson, A., Estrada, M. & Aquilonius, S.-M. (2010). Circadian rhythmicity in levodopa pharmacokinetics in patients with Parkinson disease. Clinical neuropharmacology, 33(4), 181-185
Open this publication in new window or tab >>Circadian rhythmicity in levodopa pharmacokinetics in patients with Parkinson disease
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2010 (English)In: Clinical neuropharmacology, ISSN 0362-5664, E-ISSN 1537-162X, Vol. 33, no 4, p. 181-185Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES:: The purpose of this study was to compare daytime and nighttime plasma pharmacokinetics (PK) of levodopa in patients with Parkinson disease. METHODS:: Four-hour plasma profiles of levodopa were captured in 8 patients with Parkinson disease after the second daily levodopa dose and after the identical dose at bedtime. Patients were fasting 2 hours before and 2 hours after dose intakes, except standardized amounts of tap water. Body position was upright during daytime testing and supine during nighttime testing. Four patients were additionally tested at daytime in supine position. RESULTS:: The absorption rate was significantly delayed at nighttime dosing. The time at which the maximum peaks occurred was delayed from 25 (15-240) to 105 (20-240) minutes, respectively. Maximum concentrations were significantly lower at night, but the plasma exposure (area under the curve, 0-4 hours) was unaffected. Supine daytime plasma PK was in between day and night results. CONCLUSIONS:: There is a slower absorption rate of levodopa during nighttime, probably related to delayed gastric emptying. However, the extent of absorption and bioavailability were unaffected. As the effect of posture on plasma PK was less than the effect of nighttime, this study suggests that the circadian rhythm has a pronounced effect on gastric emptying and absorption rate. Nevertheless, body position may also be an important factor, and it can be recommended that levodopa tablets be taken in upright position that probably should be sustained for at least 30 minutes.

Keywords
circadian rhythms, levodopa, nighttime, Parkinson disease, pharmacokinetics
National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:uu:diva-128957 (URN)10.1097/WNF.0b013e3181e70f7a (DOI)000280374500004 ()20661024 (PubMedID)
Available from: 2010-08-04 Created: 2010-08-04 Last updated: 2017-12-12Bibliographically approved
Johansson, A. (2009). Search for Biomarkers in ALS and Parkinson's Disease: Positron Emission Tomography and Cerebrospinal Fluid Studies. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>Search for Biomarkers in ALS and Parkinson's Disease: Positron Emission Tomography and Cerebrospinal Fluid Studies
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

New biomarkers are needed to improve knowledge about pathophysiology, in order to provide earlier correct diagnosis and to follow disease progression of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). The aim of this thesis was to find new biomarkers for these diseases.

First, increased serum levels and unchanged levels in postmortal spinal cord of vascular endothelial growth factor (VEGF) were demonstrated. VEGF was not detected in cerebrospinal fluid (CSF) in ALS. Second, increased levels of fibroblast growth factor 2 were found in the CSF and serum of ALS patients. Both studies used enzyme-linked immunoassays. Third, a proteomics method for CSF analysis was explored, based on tryptic digestion and subsequent separation and detection of the peptides by on-line liquid chromatography-Fourier transform ion cyclotron resonance mass spectrometry. ALS-specific patterns were observed. Four out of five samples were correctly assigned, but no single protein biomarker could be identified. Fourth, [11C](L)-deprenyl-D2 (DED) positron emission tomography (PET) demonstrated increased retention in the pons and white matter in ALS. DED binds to monoamino oxidase B, which in the brain is primarily located in astrocytes. Thus evidence was provided that astrocytosis may be detected in vivo in ALS.

Fifth, normal [11C]-PIB binding in five nondemented patients with PD was reported, in contrast to previous findings of increased retention in Alzheimer's disease reflecting amyloid aggregation. Finally, the combined use of fluorodeoxyglucose and L-[β 11C]-DOPA PET for the differential diagnosis of parkinsonian syndromes was evaluated. PET provided support for the clinical diagnosis in 62 out of 75 patients, and served to exclude suspected diagnoses in another five patients.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. p. 86
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 462
Series
Keywords
amyotrophic lateral sclerosis, ALS, Parkinson’s disease, cerebrospinal fluid, positron emission tomography, vascular endothelial growth factor, fibroblast growth factor 2, proteomics, Fourier transform ion cyclotron resonance mass spectrometry, deprenyl-D2, PIB, FDG, L-[β11C]-DOPA
National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:uu:diva-102040 (URN)978-91-554-7544-4 (ISBN)
Public defence
2009-06-13, Grönwallsalen, Ingång 70 bv, Akademiska sjukhuset, Uppsala, 13:15 (Swedish)
Opponent
Supervisors
Available from: 2009-05-20 Created: 2009-04-29 Last updated: 2009-05-20Bibliographically approved
Johansson, A., Savitcheva, I., Forsberg, A., Engler, H., Långström, B., Nordberg, A. & Askmark, H. (2008). [11C]-PIB imaging in patients with Parkinson's disease: preliminary results. Parkinsonism & Related Disorders, 14(4), 345-347
Open this publication in new window or tab >>[11C]-PIB imaging in patients with Parkinson's disease: preliminary results
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2008 (English)In: Parkinsonism & Related Disorders, ISSN 1353-8020, E-ISSN 1873-5126, Vol. 14, no 4, p. 345-347Article in journal (Refereed) Published
Abstract [en]

[11C]-PIB positron emission tomography ([11C]-PIB PET) is a sensitive marker of amyloid in Alzheimer's disease (AD), but its specificity has not been fully evaluated. Vascular amyloid-β deposition is common in Parkinson's disease (PD) and α-synuclein, the major component of the Lewy bodies in PD, forms amyloid fibrils. We investigated five apparently cognitively normal PD patients with [11C]-PIB PET. The results were compared to 16 patients with AD and six healthy controls from a previous study. [11C]-PIB retention was not significantly increased in our patients who all had early stage PD. Further studies of more advanced PD patients are warranted.

Keywords
Parkinson's disease, PET, PIB, Amyloid, Lewy bodies, α-Synuclein
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-16636 (URN)10.1016/j.parkreldis.2007.07.010 (DOI)000257646500015 ()
Available from: 2008-05-30 Created: 2008-05-30 Last updated: 2017-12-08Bibliographically approved
Nyholm, D., Lewander, T., Johansson, A., LeWitt, P. A., Lundqvist, C. & Aquilonius, S.-M. (2008). Enteral Levodopa/Carbidopa infusion in advanced Parkinson disease: Long-term exposure. Clinical neuropharmacology, 31(2), 63-73
Open this publication in new window or tab >>Enteral Levodopa/Carbidopa infusion in advanced Parkinson disease: Long-term exposure
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2008 (English)In: Clinical neuropharmacology, ISSN 0362-5664, E-ISSN 1537-162X, Vol. 31, no 2, p. 63-73Article in journal (Refereed) Published
Abstract [en]

Objectives: In patients with advanced Parkinson disease, levodopa/carbidopa formulated as a gel suspension (Duodopa) permits continuous delivery into the small intestine using a portable pump, resulting in less variability in levodopa concentrations and fewer motor fluctuations and dyskinesias than with oral levodopa administration. This is a retrospective analysis of the long-term clinical experience with this agent. Methods: All but 1 of the patients who had received enteral levodopa infusion treatment between January 1, 1991, and June 30, 2002, consented to a review of their hospital charts. Results: Of the 65 patients with initial testing of the treatment, 86% opted for continued treatment via percutaneous endoscopic gastrostomy or gastrojejunostomy. Total exposure to levodopa infusion was 216 patient-years (mean, 3.7 years). Maximum treatment duration was 10.7 years. Fifty-two patients were treated for 1 year or longer. The adverse effect profile of levodopa/carbidopa infusion was similar to that observed with oral administration of levodopa. Seven deaths occurred, all considered unrelated to the treatment. Intestinal tube problems, including dislocation of the intestinal tube to the stomach, were the most common technical problem, occurring in 69% of the patients during the first year. The optimal daily dose of levodopa decreased by an average of 5% during follow-up. Conclusions: The safety of enteral infusion of levodopa/ carbidopa formulated as a gel suspension was found acceptable. For most patients, the technical challenges posed by the enteral infusion system were offset by the improvement in motor fluctuations and dyskinesias offered by this technique.

Keywords
dosage, Duodopa, levodopa infusion, Parkinson, safety
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-142098 (URN)10.1097/WNF.0b013e3180ed449f (DOI)000254698200001 ()18382177 (PubMedID)
Available from: 2011-01-13 Created: 2011-01-13 Last updated: 2017-12-11Bibliographically approved
Johansson, A., Engler, H., Blomquist, G., Scott, B., Wall, A., Aquilonius, S.-M., . . . Askmark, H. (2007). Evidence for astrocytosis in ALS demonstrated by 11C(L)-deprenyl-D2 PET. Journal of the Neurological Sciences, 255(1-2), 17-22
Open this publication in new window or tab >>Evidence for astrocytosis in ALS demonstrated by 11C(L)-deprenyl-D2 PET
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2007 (English)In: Journal of the Neurological Sciences, ISSN 0022-510X, E-ISSN 1878-5883, Vol. 255, no 1-2, p. 17-22Article in journal (Refereed) Published
Abstract [en]

Objective: To use deuterium-substituted [11C](l)-deprenyl PET to depict astrocytosis in vivo in patients with amyotrophic lateral sclerosis (ALS). Background: In human brain, the enzyme MAO-B is primarily located in astrocytes. l-deprenyl binds to MAO-B and autoradiography with 3H-l-deprenyl has been used to map astrocytosis in vitro. Motor neuron loss in ALS is accompanied by astrocytosis and astrocytes may play an active role in the neurodegenerative process. Deuterium-substituted [11C](l)-deprenyl PET provides an opportunity to localize astrocytosis in vivo in the brain of patients with ALS. Methods: Deuterium-substituted [11C](l)-deprenyl PET was performed in seven patients with ALS and seven healthy control subjects. Results: Increased uptake rate of [11C](l)-deprenyl was demonstrated in ALS in pons and white matter. Conclusion: This study provides evidence that astrocytosis may be detected in vivo in ALS by the use of deuterium-substituted [11C](l)-deprenyl PET though further studies are needed to determine whether deuterium-substituted [11C](l)-deprenyl binding tracks disease progression and reflects astrocytosis.

Keywords
Amyotrophic lateral sclerosis, ALS, Motor neuron disease, Astrocytosis, PET, MAO-B, Deprenyl
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-10812 (URN)10.1016/j.jns.2007.01.057 (DOI)000245849000003 ()17346749 (PubMedID)
Available from: 2008-02-01 Created: 2008-02-01 Last updated: 2017-12-11Bibliographically approved
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