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  • 1. Bestill onlineKjøp publikasjonen >>
    Nord, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Neurologiska kliniken i Linköping.
    Levodopa pharmacokinetics -from stomach to brain: A study on patients with Parkinson’s disease2017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Parkinson’s disease (PD) is one of the most common neurodegenerative disorders and it is caused by a loss of dopamine (DA) producing neurons in the basal ganglia in the brain. The PD patient suffers from motor symptoms such as tremor, bradykinesia and rigidity and treatment with levodopa (LD), the precursor of DA, has positive effects on these symptoms. Several factors affect the availability of orally given LD. Gastric emptying (GE) is one factor and it has been shown to be delayed in PD patients resulting in impaired levodopa uptake. Different enzymes metabolize LD on its way from the gut to the brain resulting in less LD available in the brain and more side effects from the metabolites. By adding dopa decarboxylase inhibitors (carbidopa or benserazide) or COMT-inhibitors (e.g. entacapone) the bioavailability of LD increases significantly and more LD can pass the blood-brain-barrier and be converted to DA in the brain. It has been considered of importance to avoid high levodopa peaks in the brain because this seems to induce changes in postsynaptic dopaminergic neurons causing disabling motor complications in PD patients. More continuously given LD, e.g. duodenal or intravenous (IV) infusions, has been shown to improve these motor complications. Deep brain stimulation of the subthalamic nucleus (STN DBS) has also been proven to improve motor complications and to make it possible to reduce the LD dosage in PD patients.

    In this doctoral thesis the main purpose is to study the pharmacokinetics of LD in patients with PD and motor complications; in blood and subcutaneous tissue and study the effect of GE and PD stage on LD uptake and the effect of continuously given LD (CDS) on LD uptake and GE; in blood and cerebrospinal fluid (CSF) when adding the peripheral enzyme inhibitors entacapone and carbidopa to LD infusion IV; in brain during STN DBSand during oral or IV LD treatment.

    To conclude, LD uptake is more favorable in PD patients with less severe disease and GE is delayed in PD patients. No obvious relation between LD uptake and GE or between GE and PD stage is seen and CDS decreases the LD levels. Entacapone increases the maximal concentration of LD in blood and CSF. This is more evident with additional carbidopa and important to consider in avoiding high LD peaks in brain during PD treatment. LD in brain increases during both oral and IV LD treatment and the DA levels follows LD well indicating that PD patients still have capacity to metabolize LD to DA despite probable pronounced nigral degeneration. STN DBS seems to increase putaminal DA levels and together with IV LD treatment also increases LD in brain possibly explaining why it is possible to decrease LD medication after STN DBS surgery.

    Delarbeid
    1. Is Levodopa Pharmacokinetics in Patients with Parkinson’s Disease Depending on Gastric Emptying?
    Åpne denne publikasjonen i ny fane eller vindu >>Is Levodopa Pharmacokinetics in Patients with Parkinson’s Disease Depending on Gastric Emptying?
    2017 (engelsk)Inngår i: Advances in Parkinsons Disease, ISSN 2169-9712, Vol. 06, nr 01Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Levodopa uptake from the gastrointestinal tract in patients with Parkinson’s disease (PD) can be affected by delayed gastric emptying (GE). This might lead to fluctuating levodopa levels resulting in increased motor fluctuations. Continuous dopaminergic stimulation (CDS) improves motor fluctuations and could be a result of smoothening in levodopa uptake. In this study we wanted to study the levodopa pharmacokinetics peripherally in PD patients with motor fluctuations and investigate the relation between levodopa uptake and GE and the effect of CDS. PD patients with wearing off (group 1) and on-off syndrome (group 2) were included. Breath tests were performed to evaluate the half time (T1/2) of GE. Concomitantly 1 tablet of Madopark® was given and the levodopa concentrations in blood and subcutaneous (SC) tissue were analyzed for both groups. Group 2 was then given a 10-d continuous intravenous levodopa treatment and the tests were repeated. Higher levels of levodopa in group 1 compared to group 2 in blood (p = 0.014) were seen. The GE was delayed in both group 1 (p < 0.001) and group 2 (p < 0.05) compared to a reference group with healthy volunteers with T1/2 median values 105 and 78 min vs. 72 min. There was no difference in GE between the two PD groups (p = 0.220) or in group 2 before and after infusion period (p = 0.861). CDS resulted in lower levodopa levels in blood (p < 0.001) and SC tissue (p < 0.01). In conclusion, PD patients in early complication phase have a more favourable levodopa uptake than patients later in disease. We found delayed GE in PD patients with motor fluctuations but no obvious relation between GE and levodopa uptake or GE and PD stage. The effect of CDS indicates no effect of CDS on the mechanisms of GE but on the mechanisms of levodopa uptake.

    sted, utgiver, år, opplag, sider
    Scientific Research Publishing, 2017
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-136685 (URN)10.4236/apd.2017.61001 (DOI)
    Tilgjengelig fra: 2017-04-20 Laget: 2017-04-20 Sist oppdatert: 2018-01-12
    2. The Effect of Peripheral Enzyme Inhibitors on Levodopa Concentrations in Blood and CSF
    Åpne denne publikasjonen i ny fane eller vindu >>The Effect of Peripheral Enzyme Inhibitors on Levodopa Concentrations in Blood and CSF
    Vise andre…
    2010 (engelsk)Inngår i: Movement Disorders, ISSN 0885-3185, E-ISSN 1531-8257, Vol. 25, nr 3, s. 363-367Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Levodopa combined with a dopa-decarboxylase inhibitor, such as carbidopa. shifts the metabolism to the COMT pathway. Adding the peripheral acting COMT inhibitor entacapone provides improvement for patients with PD suffering from motor fluctuations. We studied the effects of the enzyme inhibitors entacapone and carbidopa on the levodopa concentrations in CSF and in blood. Five PD patients with wearing-off underwent lumbar drainage and intravenous microdialysis. Samples were taken 12 h daily for 3 days. Day I; intravenous levodopa was given, day 2; additional oral entacapone 200 mg tid, day 3; additional oral entacapone 200 mg bid and carbidopa 25 mg bid. Levodopa in CSF and in dialysates was analysed. The AUC for levodopa increased both in blood and CSF when additional entacapone was given alone and in combination with carbidopa. The C-max of levodopa in both CSF and blood increased significantly. Additional entacapone to levodopa therapy gives an increase of C-max in CSF and in blood. The increase is more evident when entacapone is combined with carbidopa.

    sted, utgiver, år, opplag, sider
    John Wiley & Sons, 2010
    Emneord
    Parkinsons Disease, levodopa, continuous infusion, COMT
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-54855 (URN)10.1002/mds.22613 (DOI)000276136900016 ()
    Tilgjengelig fra: 2010-04-16 Laget: 2010-04-16 Sist oppdatert: 2018-01-12
    3. Neurotransmitter levels in basal ganglia during levodopa and deep brain stimulation treatment in Parkinson’s disease
    Åpne denne publikasjonen i ny fane eller vindu >>Neurotransmitter levels in basal ganglia during levodopa and deep brain stimulation treatment in Parkinson’s disease
    Vise andre…
    2014 (engelsk)Inngår i: Neurology and Clinical Neuroscience, ISSN 2049-4173, Vol. 2, nr 5, s. 149-155Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background The mechanism by which deep brain stimulation of the nucleus subthalamicus improves Parkinson’s disease symptoms remains unclear. In a previous perioperative study, we showed that there might be alterations of neurotransmitter levels in the globus pallidum interna during deep brain stimulation of the nucleus subthalamicus. Aim In this study, we examined whether deep brain stimulation of the nucleus subthalamicus and levodopa infusion interact and affect the levels of neurotransmitters. Methods Five patients with advanced Parkinson’s disease took part in the study. During subthalamic nucleus surgery, microdialysis catheters were inserted bilaterally in the globus pallidum interna and unilaterally in the right putamen. A study protocol was set up and was followed for 3 days. Levodopa infusion with and without concomitant bilateral deep brain stimulation of the nucleus subthalamicus was also carried out. Results The putaminal dopamine levels increased during deep brain stimulation of the nucleus subthalamicus. In addition, an increase of gamma amino buturic acid concentrations in the globus pallidum interna during deep brain stimulation of the nucleus subthalamicus and during levodopa infusion was found. Conclusions These findings provide evidence that the subthalamic nucleus has a direct action on the substantia nigra pars compacta, and that deep brain stimulation of the nucleus subthalamicus might indirectly release putaminal dopamine. There is also evidence that deep brain stimulation of the nucleus subthalamicus interferes with levodopa therapy resulting in higher levels of levodopa in the brain, explaining why it is possible to decrease levodopa medication after deep brain stimulation surgery.

    sted, utgiver, år, opplag, sider
    John Wiley & Sons, 2014
    Emneord
    deep brain stimulation, levodopa, microdialysis, neurotransmitters, Parkinson
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-113590 (URN)10.1111/ncn3.109 (DOI)
    Tilgjengelig fra: 2015-01-23 Laget: 2015-01-23 Sist oppdatert: 2019-02-11bibliografisk kontrollert
    4. Levodopa Pharmacokinetics in Brain after Both Oral and Intravenous Levodopa in One Patient with Advanced Parkinson’s Disease
    Åpne denne publikasjonen i ny fane eller vindu >>Levodopa Pharmacokinetics in Brain after Both Oral and Intravenous Levodopa in One Patient with Advanced Parkinson’s Disease
    2017 (engelsk)Inngår i: Advances in Parkinsons Disease, ISSN 2169-9712, Vol. 6, nr 2, s. 52-66Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Objective: One patient received oral levodopa during a study aiming for better understanding of the basal ganglia and of the mechanisms of deep brain stimulation of the subthalamic nucleus (STN DBS) with and without intravenous (IV) levodopa infusion in patients with Parkinson’s disease (PD). The results from oral and IV levodopa treatment are presented.

    Methods: Five patients with advanced PD were included in the original study. During planned STN DBS surgery microdialysis probes were implanted in the right putamen and in the right and left globus pallidus interna (Gpi). During the study, microdialysis was performed continuously and STN DBS, with and without IV levodopa infusion, was performed according to a specific protocol. After DBS surgery, but before STN DBS was started, one patient received oral levodopa/ benserazide and entacapone tablets out of protocol due to distressing parkinsonism.

    Results: The levodopa levels increased prompt in the central nervous system after the first PD medication intakes but declined after the last. Immediately the levodopa seemed to be metabolized to dopamine (DA) since the levels of DA correlated well with levodopa concentrations. Left STN DBS seemed to further increase DA levels in left Gpi while right STN DBS seemed to increase DA levels in the right putamen and right Gpi. There was no obvious effect on levodopa levels.

    Conclusions: The results indicate that PD patients still have capacity to metabolize levodopa to DA despite advanced disease with on-off symptoms and probably pronounced nigral degeneration. STN DBS seems to increase DA levels with a more pronounced effect on ipsilateral structures in striatum.

    sted, utgiver, år, opplag, sider
    Scientific Research Publishing Inc, 2017
    Emneord
    Parkinson’s Disease, Levodopa, Dopamine, Brain, Microdialysis, Deep Brain Stimulation
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-139251 (URN)10.4236/apd.2017.62006 (DOI)
    Tilgjengelig fra: 2017-07-07 Laget: 2017-07-07 Sist oppdatert: 2018-01-12bibliografisk kontrollert
  • 2.
    Nord, Maria
    et al.
    Region Östergötland, Närsjukvården i centrala Östergötland, Neurologiska kliniken.
    Zsigmond, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Neurokirurgiska kliniken US.
    Kullman, Anita
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Dizdar Segrell, Nil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Neurologiska kliniken.
    Levodopa Pharmacokinetics in Brain after Both Oral and Intravenous Levodopa in One Patient with Advanced Parkinson’s Disease2017Inngår i: Advances in Parkinsons Disease, ISSN 2169-9712, Vol. 6, nr 2, s. 52-66Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: One patient received oral levodopa during a study aiming for better understanding of the basal ganglia and of the mechanisms of deep brain stimulation of the subthalamic nucleus (STN DBS) with and without intravenous (IV) levodopa infusion in patients with Parkinson’s disease (PD). The results from oral and IV levodopa treatment are presented.

    Methods: Five patients with advanced PD were included in the original study. During planned STN DBS surgery microdialysis probes were implanted in the right putamen and in the right and left globus pallidus interna (Gpi). During the study, microdialysis was performed continuously and STN DBS, with and without IV levodopa infusion, was performed according to a specific protocol. After DBS surgery, but before STN DBS was started, one patient received oral levodopa/ benserazide and entacapone tablets out of protocol due to distressing parkinsonism.

    Results: The levodopa levels increased prompt in the central nervous system after the first PD medication intakes but declined after the last. Immediately the levodopa seemed to be metabolized to dopamine (DA) since the levels of DA correlated well with levodopa concentrations. Left STN DBS seemed to further increase DA levels in left Gpi while right STN DBS seemed to increase DA levels in the right putamen and right Gpi. There was no obvious effect on levodopa levels.

    Conclusions: The results indicate that PD patients still have capacity to metabolize levodopa to DA despite advanced disease with on-off symptoms and probably pronounced nigral degeneration. STN DBS seems to increase DA levels with a more pronounced effect on ipsilateral structures in striatum.

  • 3.
    Nord, Maria
    et al.
    Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Neurologiska kliniken.
    Zsigmond, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Neurokirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Neurokirurgiska kliniken US.
    Kullman, Anita
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
    Årstrand, Kerstin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
    Dizdar (Dizdar Segrell), Nil
    Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Neurologiska kliniken. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    The Effect of Peripheral Enzyme Inhibitors on Levodopa Concentrations in Blood and CSF2010Inngår i: Movement Disorders, ISSN 0885-3185, E-ISSN 1531-8257, Vol. 25, nr 3, s. 363-367Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Levodopa combined with a dopa-decarboxylase inhibitor, such as carbidopa. shifts the metabolism to the COMT pathway. Adding the peripheral acting COMT inhibitor entacapone provides improvement for patients with PD suffering from motor fluctuations. We studied the effects of the enzyme inhibitors entacapone and carbidopa on the levodopa concentrations in CSF and in blood. Five PD patients with wearing-off underwent lumbar drainage and intravenous microdialysis. Samples were taken 12 h daily for 3 days. Day I; intravenous levodopa was given, day 2; additional oral entacapone 200 mg tid, day 3; additional oral entacapone 200 mg bid and carbidopa 25 mg bid. Levodopa in CSF and in dialysates was analysed. The AUC for levodopa increased both in blood and CSF when additional entacapone was given alone and in combination with carbidopa. The C-max of levodopa in both CSF and blood increased significantly. Additional entacapone to levodopa therapy gives an increase of C-max in CSF and in blood. The increase is more evident when entacapone is combined with carbidopa.

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Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Annet format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
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  • sv-SE
  • Annet språk
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