A Double-Blind Pharmacokinetic and Clinical Dose—Response Study of Entacapone as an Adjuvant to Levodopa Therapy in Advanced Parkinson's Disease

Aims:To assess the efficacy and safety of adjuvant treatment with entacapone in the treatment of later Parkinson's disease (PD) patients with motor fluctuation. Methods: We conducted a systematic review of relevant studies from 8 databases to June 23, 2016. Results: Fourteen studies were included in this review (n = 2,804). The results showed that compared with placebo, adjuvant therapy with entacapone significantly increased on time (p < 0.01) and reduced off time (p < 0.01), the required levodopa (LD) dose (p < 0.01) and improved Parkinson's Disease Rating Scale (UPDRS) scores (activities of daily living score: p < 0.01; motor score: p < 0.01; UPDRS I-III score: p > 0.05). However, the withdrawal (OR 1.44, 95% CI 1.10-1.89, p < 0.01) due to adverse events and adverse events rates including nausea (OR 2.23, 95% CI 1.56-3.20, p < 0.01), urine discoloration (OR 14.99,, p < 0.01), gastrointestinal disorder (OR 2.6, 95% CI 1.89-3.57, p < 0.01) and dyskinesia (OR 2.00, 95% CI 1.56-2.58, p < 0.01) increased in patients with entacapone compared with those given a placebo . Conclusions: This metaanalysis suggests that the entacapone used as adjuvant therapy to LD is effective in the management of later PD with fluctuation. However, patients on entacapone had a higher frequency of adverse events than those on placebo but no occurrence of severe adverse reactions.

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“…Finally, 14 studies were included in this meta-analysis ( Fig. 1) [14,[18][19][20][21][22][23][24][25][26][27][28][29][30].…”

Section: Characteristics and Quality Of Studiesmentioning

confidence: 99%

“…Among the 14 studies, the motor complications, including the "on" and "off" phenomena were observed in 12 [14,[18][19][20][21][24][25][26][27][28][29][30] and 9 studies [14, 18-20, 22, 25-27, 30], respectively. Overall, forest plots of the motor complications between placebo and adjuvant therapy are shown in Figure 2.…”

Section: The Efficacy Of Entacapone For Pdmentioning

confidence: 99%

Efficacy and Safety of Adjuvant Treatment with Entacapone in Advanced Parkinson’s Disease with Motor Fluctuation: A Systematic Meta-Analysis

Lou

Liu

et al. 2017

Eur Neurol

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“…There are some possible explanations why our results concerning levodopa C max differ from previous studies. For example, entacapone was only given as a single-dose together with levodopa/DDI in some of these studies (60,62), while in our study entacapone was given at 4-h intervals, more similar to the clinical situation for PD patients treated with additional entacapone. In their study, Kaakkola et al gave additional entacapone to each dose of levodopa, but blood samples were only taken after the first morning dose (59), while we collected samples for 12 h. Our results showed an increase of levodopa C max in both CSF and in blood, and this is important to take into consideration when starting additional treatment with entacapone to levodopa/DDI.…”

Section: Discussionmentioning

confidence: 93%

“…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%

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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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Double-blind, Placebo-Controlled Study of Entacapone in Levodopa-Treated Patients With Stable Parkinson Disease

Olanow

Kieburtz²,

Stern³

et al. 2004

Arch Neurol

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A Double-Blind Pharmacokinetic and Clinical Dose—Response Study of Entacapone as an Adjuvant to Levodopa Therapy in Advanced Parkinson's Disease

Cited by 115 publications

References 0 publications

Efficacy and Safety of Adjuvant Treatment with Entacapone in Advanced Parkinson’s Disease with Motor Fluctuation: A Systematic Meta-Analysis

Efficacy and Safety of Adjuvant Treatment with Entacapone in Advanced Parkinson’s Disease with Motor Fluctuation: A Systematic Meta-Analysis

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

Double-blind, Placebo-Controlled Study of Entacapone in Levodopa-Treated Patients With Stable Parkinson Disease

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