Effect of entacapone, a COMT inhibitor, on clinical disability and levodopa metabolism in parkinsonian patients

Kaakkola, Seppo; Teräväinen, H.; Ahtila, S.; Rita, H.; Gordin, A.

doi:10.1212/wnl.44.1.77

Cited by 107 publications

(72 citation statements)

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“…However, in later-stage patients with wearing-off symptoms with or without existing dyskinesia, enhancing dopaminergic therapy with any oral medication will often increase dyskinesia to some extent in addition to expected antiparkinsonian effects. This is true also for enhancement of levodopa therapy with COMT-inhibitors [7,10,[23][24].…”

Section: Discussionmentioning

confidence: 99%

Comparison of pharmacokinetic profile of levodopa throughout the day between levodopa/carbidopa/entacapone and levodopa/carbidopa when administered four or five times daily

Kuoppamäki

Korpela

Marttila

et al. 2009

Eur J Clin Pharmacol

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Objectives To compare plasma levodopa concentrations after repeated doses of levodopa/carbidopa/entacapone (LCE) and levodopa/carbidopa (LC). Methods Open-label, randomized, two-period, activecontrolled, cross-over study with four dosing regimens: groups I and II (healthy volunteers and Parkinson's disease patients) received levodopa 100 mg or 150 mg four times daily, respectively, and groups III and IV (healthy volunteers) received the same strengths of levodopa five times daily. Pharmacokinetic (PK) parameters determined for levodopa included C min , C max , C max −C min , AUC, t 1/2 , and t max .Results In healthy volunteers and PD patients, mean trough levels (C min ), C max , and AUC of levodopa were, in general, significantly higher during LCE compared to LC administration. Compared to C min , C max , and AUC, differences between the treatments in variability of levodopa concentrations (C max −C min ) were less consistent. Conclusions The present results on the differences in levodopa PK between LCE and LC provide a basis to evaluate the relationship of levodopa PK and the induction of motor complications in an on-going study in early Parkinson's disease using similar dosing regimens.

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Section: Discussionmentioning

confidence: 99%

Comparison of pharmacokinetic profile of levodopa throughout the day between levodopa/carbidopa/entacapone and levodopa/carbidopa when administered four or five times daily

Kuoppamäki

Korpela

Marttila

et al. 2009

Eur J Clin Pharmacol

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“…5) COMT inhibitor, such as entacapone, increases the area under the L-DOPA plasma concentration-time curve 6) and thus prolongs its clinical effect. 7) 3-OMD inhibits distribution of L-DOPA into the brain, since 3-OMD competes with L-DOPA at the blood-brain barrier transporter system. 8) In addition, 3-OMD might inhibit DA release because DA efflux from striatal tissue slices was significantly reduced after L-DOPA superfusion with 3-OMD.…”

Section: 3)mentioning

confidence: 99%

Effects of 3-<i>O</i>-Methyldopa, <small>L</small>-3,4-Dihydroxyphenylalanine Metabolite, on Locomotor Activity and Dopamine Turnover in Rats

Onzawa

Kimura

Uzuhashi

et al. 2012

Biological & Pharmaceutical Bulletin

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It has been well known that 3-O-methyldopa (3-OMD) is a metabolite of L-3,4-dihydroxyphenylalanine (L-DOPA) formed by catechol O-methyltransferase (COMT), and 3-OMD blood level often reaches higher than physiological level in Parkinson's disease (PD) patients receiving long term L-DOPA therapy. However, the physiological role of 3-OMD has not been well understood. Therefore, in order to clarify the effects of 3-OMD on physiological function, we examined the behavioral alteration in rats based on locomotor activity, and measured dopamine (DA) and its metabolites levels in rats at the same time after 3-OMD subchronic administration. The study results showed that repeated administrations of 3-OMD increased its blood and the striatum tissue levels in those rats, and decreased locomotor activity in a dose dependent manner. Although 3-OMD subchronic administration showed no significant change in DA level in the striatum, DA metabolite levels, such as 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT), and homovanillic acid (HVA) were significantly decreased. After 3-OMD washout period (7 d), locomotor activity and DA turnover in those rats returned to normal levels. Furthermore, locomotor activity and DA turnover decreased by 3-OMD administration were recovered to normal level by acute L-DOPA administration. These results suggested that 3-OMD affect to locomotor activity via DA neuron system. In conclusion, 3-OMD itself may have a disadvantage in PD patients receiving L-DOPA therapy.Key words 3-O-methyldopa; L-3,4-dihydroxyphenylalanine; locomotor activity; dopamine turnover; rat Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons in the substantia nigra region of the basal ganglia, which results in movement-related symptoms. Current treatment for PD includes dopamine replacement therapy in the form of L-3,4-dihydroxyphenylalanine (L-DOPA), a precursor to dopamine (DA) in its synthesis pathway that has been the gold standard of care for decades. More recently, DA receptor agonists, such as pramipexole, pergolide, and ropinirole, have become more commonly prescribed for the treatment of PD. Approximately 50% of PD patients, when treated with L-DOPA for more than 5 years, experience motor fluctuations such as the "wearing-off" phenomenon or the "no-on" phenomenon. 1) L-DOPA is commonly administered with aromatic amino acid decarboxylase (AADC) inhibitor, such as carbidopa or benserazide. 3-O-methyldopa (3-OMD) is a major metabolite of L-DOPA. 3-OMD is formed by catechol O-methyltransferase (COMT) in many organs including blood, peripheral tissues and brain.2) 3-OMD easily accumulates in several tissues (liver, kidney, brain, blood) because 3-OMD has much longer half-life (approximately 15 h) than L-DOPA. 2,3)It is reported that L-DOPA upregulates the expression and activity of COMT. 4) Therefore, blood level of 3-OMD is continually high and 3-OMD accumulates in PD patients receiving long term L-DOPA therapy.5) COMT inhibitor, such as entacapone, increases the area under ...

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“…It also seemed as if levodopa was accumulated extracellularly in brain and this could indicate a longer T½ of levodopa in brain compared to peripheral blood. Both the DDI benserazide and the COMT-inhibitor entacapone were given during the period of oral medication and adding a DDI or entacapone to levodopa have previously been shown to increase the T½ of levodopa in blood (35,(58)(59)(60)(61)(62). Adding the COMT-inhibitor entacapone to levodopa/DDI also results in higher levels of levodopa in brain (66).…”

Section: Discussionmentioning

confidence: 99%

“…The COMTinhibitor entacapone has been shown to increase [18F]-6-L-fluorodopa in striatum in PD patients with premedication with the DDI carbidopa (66). Several studies have stated that the addition of entacapone does not increase the C max of levodopa (59,60,62,(67)(68)(69)(70) in the periphery with the conclusion that the same applies for the brain.…”

Section: Levodopa In the Brainmentioning

confidence: 99%

Levodopa pharmacokinetics -from stomach to brain : A study on patients with Parkinson’s disease

Nord¹

2017

Linköping University Medical Dissertations

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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.Parkinsons sjukdom (PS) är en av de vanligaste s.k. neurodegenerativasjukdomarna och orsakas av förlust av dopamin(DA)producerande nervceller i hjärnan. Detta orsakar motoriska symptom såsom skakningar, stelhet och förlångsammade rörelser. Levodopa (LD) är ett ämne, som kan omvandlas till DA i hjärnan och ge symptomlindrin...

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Effect of entacapone, a COMT inhibitor, on clinical disability and levodopa metabolism in parkinsonian patients

Cited by 107 publications

References 0 publications

Comparison of pharmacokinetic profile of levodopa throughout the day between levodopa/carbidopa/entacapone and levodopa/carbidopa when administered four or five times daily

Comparison of pharmacokinetic profile of levodopa throughout the day between levodopa/carbidopa/entacapone and levodopa/carbidopa when administered four or five times daily

Effects of 3-<i>O</i>-Methyldopa, <small>L</small>-3,4-Dihydroxyphenylalanine Metabolite, on Locomotor Activity and Dopamine Turnover in Rats

Levodopa pharmacokinetics -from stomach to brain : A study on patients with Parkinson’s disease

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