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Aquilonius, Sten-Magnus
Publications (10 of 40) Show all publications
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
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
Nyholm, D., Ehrnebo, M., Lewander, T., Trolin, C. G., Bäckström, T., Panagiotidis, G., . . . Aquilonius, S.-M. (2013). Frequent administration of levodopa/carbidopa microtablets vs levodopa/carbidopa/entacapone in healthy volunteers. Acta Neurologica Scandinavica, 127(2), 124-132
Open this publication in new window or tab >>Frequent administration of levodopa/carbidopa microtablets vs levodopa/carbidopa/entacapone in healthy volunteers
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2013 (English)In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 127, no 2, p. 124-132Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES:

An oral dispersible microtablet formulation of levodopa/carbidopa 5/1.25 mg (LC-5) was developed for individualized repeated dosing. The aim was to compare pharmacokinetic profiles of LC-5 and levodopa/carbidopa/entacapone (LCE).

MATERIALS AND METHODS:

A randomized, crossover study was carried out in 11 healthy subjects. Plasma concentrations of levodopa, carbidopa and 3-O-methyldopa were determined after intake of 300 mg levodopa during the day, either as three intakes of 100/25/200 mg LCE or as a morning dose of 75/18.25 mg followed by five repeated doses of 45/11.25 mg LC-5.

RESULTS:

Repeated dosing (2.4-hourly) with LC-5 microtablets compared to LCE (6-hourly) avoided long periods with low plasma levodopa levels. Time to maximum plasma concentrations was significantly shorter for LC-5. LC-5 showed lower fluctuation index (FI) in plasma compared to LCE (ANOVA P = 0.0028). FI for dose 2-5 was on average 1.26 for levodopa in LC-5, and 2.23 for dose 1-2 of LCE. The ratio between the two mean FI:s is 0.565; that is, LC-5 gave nearly half the FI as compared to LCE.

CONCLUSIONS:

Fractionation of levodopa with LC-5 into small, frequent administrations as compared to standard administrations of LCE decreased the FI in plasma for both levodopa and carbidopa by nearly half.

National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:uu:diva-188647 (URN)10.1111/j.1600-0404.2012.01700.x (DOI)000313886700009 ()22762460 (PubMedID)
Available from: 2012-12-18 Created: 2012-12-18 Last updated: 2017-12-06Bibliographically approved
Sikk, K., Haldre, S., Aquilonius, S.-M., Asser, A., Paris, M., Roose, A., . . . Taba, P. (2013). Manganese-induced parkinsonism in methcathinone abusers: bio-markers of exposure and follow-up. European Journal of Neurology, 20(6), 915-920
Open this publication in new window or tab >>Manganese-induced parkinsonism in methcathinone abusers: bio-markers of exposure and follow-up
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2013 (English)In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 20, no 6, p. 915-920Article in journal (Refereed) Published
Abstract [en]

Background and purpose Methcathinone abuse is a new cause of manganism. The psychostimulant is prepared from pseudoephedrine using potassium permanganate as an oxidant. We describe the clinical, biological, neuroimaging characteristics and follow-up results in a large Estonian cohort of intravenous methcathinone users. Methods During 20062012 we studied 38 methcathinone abusers with a mean age of 33years. Subjects were rated by the Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn and Yahr (HY), and Schwab and England (SE) rating scales. Twenty-four cases were reassessed 970 (20 +/- 15)months after the initial evaluation. Manganese (Mn) in plasma and hair was analysed by inductively coupled plasma-atom emission spectrometry. Magnetic resonance imaging (MRI) was performed in 11, and single-photon emission computed tomography (SPECT) with iodobenzamide (IBZM) in eight subjects. Results The average total UPDRS score was 43 +/- 21. The most severely affected domains in UPDRS Part III were speech and postural stability, the least affected domain was resting tremor. At follow-up there was worsening of HY and SE rating scales. Subjects had a higher mean level of Mn in hair (2.9 +/- 3.8ppm) than controls (0.82 +/- 1.02ppm), P=0.02. Plasma Mn concentrations were higher (11.5 +/- 6.2ppb) in active than in former users (5.6 +/- 1.8ppb), P=0.006. Active methcathinone users had increased MRI T1-signal intensity in the globus pallidus, substantia nigra and periaquaductal gray matter. IBZM-SPECT showed normal symmetric tracer uptake in striatum. Conclusion Methcathinone abusers develop a distinctive hypokinetic syndrome. Though the biomarkers of Mn exposure are characteristic only of recent abuse, the syndrome is not reversible.

Keywords
ephedrone, follow-up, manganism, methcathinone, MRI hyperintensities, parkinsonism
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-201779 (URN)10.1111/ene.12088 (DOI)000318800600013 ()
Available from: 2013-06-17 Created: 2013-06-17 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
Sikk, K., Haldre, S., Aquilonius, S.-M., Petterson, J., Eriksson, S.-L. -., Bergquist, J., . . . Taba, P. (2012). Manganese-induced parkinsonism in methcathinone abusers: biomarkers of exposure and follow-up. Paper presented at 16th Congress of the European-Federation-of-Neurological-Societies (EFNS), SEP 08-11, 2012, Stockholm, SWEDEN. European Journal of Neurology, 19, 667-667
Open this publication in new window or tab >>Manganese-induced parkinsonism in methcathinone abusers: biomarkers of exposure and follow-up
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2012 (English)In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 19, p. 667-667Article in journal, Meeting abstract (Other academic) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-184738 (URN)000309359704157 ()
Conference
16th Congress of the European-Federation-of-Neurological-Societies (EFNS), SEP 08-11, 2012, Stockholm, SWEDEN
Available from: 2012-11-15 Created: 2012-11-13 Last updated: 2017-12-07Bibliographically approved
Aquilonius, S.-M. (2012). Parkinson's disease: Swedish pioneering research on pathophysiology and treatment. Paper presented at 16th Congress of the European-Federation-of-Neurological-Societies (EFNS), SEP 08-11, 2012, Stockholm, SWEDEN. European Journal of Neurology, 19(S1), 841-841
Open this publication in new window or tab >>Parkinson's disease: Swedish pioneering research on pathophysiology and treatment
2012 (English)In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 19, no S1, p. 841-841Article in journal, Meeting abstract (Other academic) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-184741 (URN)000309359705292 ()
Conference
16th Congress of the European-Federation-of-Neurological-Societies (EFNS), SEP 08-11, 2012, Stockholm, SWEDEN
Available from: 2012-11-14 Created: 2012-11-13 Last updated: 2017-12-07Bibliographically approved
Nyholm, D., Lewander, T., Gomes-Trolin, C., Bäckström, T., Panagiotidis, G., Ehrnebo, M., . . . Aquilonius, S.-M. (2012). Pharmacokinetics of levodopa/carbidopa microtablets versus levodopa/benserazide and levodopa/carbidopa in healthy volunteers. Clinical neuropharmacology, 35(3), 111-117
Open this publication in new window or tab >>Pharmacokinetics of levodopa/carbidopa microtablets versus levodopa/benserazide and levodopa/carbidopa in healthy volunteers
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2012 (English)In: Clinical neuropharmacology, ISSN 0362-5664, E-ISSN 1537-162X, Vol. 35, no 3, p. 111-117Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: To compare bioavailability and pharmacokinetics of single doses of 3 different levodopa formulations given orally in healthy volunteers. Two marketed formulations, standard levodopa/carbidopa, 100/25 mg (LC-100), and dispersible levodopa/benserazide, 100/25 mg (LB-100), were used as reference formulations for a newly developed dispersible microtablet formulation of levodopa/carbidopa, 5/1.25 mg (LC-5). The microtablets are intended for individualized dosing of levodopa/carbidopa in Parkinson disease by means of an electronic dose dispenser with a built-in diary for symptom registration.

METHODS: A single-dose, open, randomized, 3-way crossover study was performed in 19 healthy subjects. Concentrations of levodopa, carbidopa, and the metabolite 3-O-MD in plasma were determined after intake of 100 mg of levodopa, that is, one tablet of reference formulations and 20 microtablets of the new formulation.

RESULTS: The LC-5 microtablets were bioequivalent to the LC-100 tablets in area under the curve (AUC) and maximum concentration in plasma (Cmax) for levodopa, and to the LB-100 tablets in AUC. The dispersible levodopa/benserazide formulation showed earlier time to Cmax and significantly higher Cmax for levodopa in plasma compared to the microtablets. Carbidopa showed larger interindividual variation in AUC and Cmax than levodopa, and the bioequivalence comparison LC-5/LC-100 for this compound did not reach the target. Nevertheless, comparison of 3-O-MD levels for LC-5/LC-100, assuming proportionality to levodopa levels, demonstrated bioequivalence.

CONCLUSIONS: The new levodopa/carbidopa microtablets had a pharmacokinetic profile that would allow for a convenient switch of therapy from standard tablets. Frequent dose administration of levodopa/carbidopa microtablets with an electronic dose dispenser might offer an optimal oral drug delivery in Parkinson disease.

Keywords
Parkinson disease, levodopa/carbidopa, levodopa/benserazide, pharmacokinetics, microtablets
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-174562 (URN)10.1097/WNF.0b013e31825645d1 (DOI)000304365500003 ()22549097 (PubMedID)
Available from: 2012-05-22 Created: 2012-05-22 Last updated: 2017-12-07Bibliographically 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
Zetterberg, L., Aquilonius, S.-M. & Lindmark, B. (2009). Impact of dystonia on quality of life and health in a Swedish population. Acta Neurologica Scandinavica, 119(6), 376-382
Open this publication in new window or tab >>Impact of dystonia on quality of life and health in a Swedish population
2009 (English)In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 119, no 6, p. 376-382Article in journal (Refereed) Published
Abstract [en]

Objectives –  Dystonia is often disabling and disfiguring. The aim of the study was to identify factors influencing the impact of dystonia on self-reported quality of life and health.

Material and methods –  Members of the Swedish Dystonia Patient Association participated in a survey covering demographic variables, satisfaction with treatment, physiotherapy and physical activity. Quality of life and health were assessed by the Craniocervical Dystonia Questionnaire and the Cervical Dystonia Impact Profile, respectively. Of 378 questionnaires, 76% were analysed. Multiple linear regression analyses were performed to evaluate associations of the above variables with quality of life and health.

Results –  Level of physical activity and satisfaction with treatment showed the highest association with quality of life and health. No significant relationship was found between form of dystonia and quality of life.

Conclusions –  The study indicates a need for health care professionals to encourage physical activity and to question dystonia patients about satisfaction with treatment. Further investigations with prospective controlled trials are necessary to evaluate the value of physiotherapy and physical activity in patients with dystonia.

Keywords
dystonia, healt, quality of life
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-97888 (URN)10.1111/j.1600-0404.2008.01111.x (DOI)000266014600005 ()
Available from: 2008-11-28 Created: 2008-11-28 Last updated: 2017-12-14Bibliographically approved
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