entacapone and Hyperhomocysteinemia

Levodopa remains the mainstay treatment for Parkinson's disease (PD). Chronic treatment is associated with motor complications (MC) that marred the clinical benefit of levodopa. These problems and experimental data in cell cultures indicating a neurotoxic effect of levodopa have led to the idea of delaying the introduction of levodopa treatment for as long as possible. We here review recent data regarding the mechanism of action of levodopa and its application in clinical practice on the light of the marketing of the combination levodopa-carbidopa- entacapone. Accumulated evidence indicates that MC are mainly the consequence of disease severity governing the degree of dopaminergic depletion and the "pulsatile" dopaminergic stimulation provided by levodopa short plasma half-life. There is no in vivo or clinical evidence of a relevant neurotoxic effect of levodopa. In fact, the recent ELLDOPA study may suggest a neuroprotective effect. Entacapone reduces homocysteine plasma levels which could provide a mechanism to reduce cell death in PD. Currently, the combination levodopa-carbidopa-entacapone is particularly indicated for the treatment of "wearing off" fluctuations. Experimental evidence suggests that early treatment with levodopa-carbidopa-entacapone may substantially ameliorate the incidence of MC. Such a clinical study in "de novo" patients is underway. At present, the combination levodopa-carbidopa-entacapone is indicated when levodopa is judged necessary.

Topics: Akathisia, Drug-Induced; Animals; Antiparkinson Agents; Carbidopa; Catechols; Clinical Trials as Topic; Dopamine; Drug Therapy, Combination; Humans; Hyperhomocysteinemia; Levodopa; MPTP Poisoning; Neuroprotective Agents; Nitriles; Parkinson Disease; Parkinsonian Disorders; Rats; Treatment Outcome

Previous studies have suggested a significant increase in plasma homocysteine (Hcy) levels in levodopa-treated Parkinson's disease (PD) patients, and vitamin B12 and folate supplementation may decrease Hcy levels. However, the effects of catechol-O-methyltransferase inhibitors on levodopa-induced increase in Hcy levels were conflicting. The aim of this study was to evaluate whether Hcy levels are increased in levodopa-treated PD patients and to evaluate the effects of vitamin B12 and folate or entacapone on Hcy levels in levodopa-treated PD patients.. We analyzed and compared plasma Hcy levels in 20 levodopa-naïve PD patients and 42 levodopa-treated PD patients, followed by randomized assignment of 42 levodopa-treated patients to treatment groups with either vitamin B12 and folate, entacapone, or no medication.. Plasma Hcy levels in levodopa-treated PD patients were higher than those in the control group, but the difference was not statistical significant (15.25 ± 6.70 and 13.13 ± 4.68, P = 0.216). Patients treated with vitamin B12 and folate had a significant decrease in plasma Hcy levels (P < 0.001). In the entacapone group, Hcy levels were mildly decreased, but the change did not reach statistical significance.. Levodopa-treated PD patients had higher plasma Hcy than levodopa-naive PD patients. Unlike entacapone, combination supplementation with vitamin B12 and folate was associated with significantly decreased plasma Hcy. We suggest that plasma Hcy levels should be monitored during levodopa treatment, and supplementation with inexpensive vitamin B12 and folate is beneficial for levodopa-treated patients.

Topics: Aged; Antiparkinson Agents; Catechols; Female; Folic Acid; Homocysteine; Humans; Hyperhomocysteinemia; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Research Design; Vitamin B 12

Plasma homocysteine (Hcy) levels may increase in levodopa-treated patients with Parkinson's disease (PD) as a consequence of levodopa methylation via catechol-O-methyltransferase (COMT). Results from previous studies that assessed the effect of COMT inhibitors on levodopa-induced hyperhomocysteinemia are conflicting. We aimed to evaluate the effects of levodopa and entacapone on plasma Hcy levels. A hundred PD patients were enrolled to the study and divided into three treatment groups (group I: levodopa and/or dopamine agonists; group II: levodopa, entacapone, and/or a dopamine agonist; and group III: dopamine agonist alone). We measured the serum B12, folic acid, and Hcy levels in all patients. There were no statistically significant differences between groups in terms of modified Hoehn and Yahr stages, Unified Parkinson's Disease Rating Scale II/III, Standardized Mini-Mental Test scores, and serum vitamin B12 and folic acid levels. Plasma median Hcy levels were found above the normal laboratory values in groups I and II, but they were normal in group III. However, there was no statistically significant difference in plasma Hcy levels between groups. Our results showed that levodopa treatment may cause a slight increase in the Hcy levels in PD compared with dopamine agonists and that COMT inhibitors may not have a significant effect on preventing hyperhomocysteinemia.

Topics: Adult; Aged; Aged, 80 and over; Catechol O-Methyltransferase; Catechols; Dopamine Agonists; Female; Homocysteine; Humans; Hyperhomocysteinemia; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Prospective Studies

Elevated homocysteine is associated with increased risk of heart disease, stroke, and dementia. Therapy of Parkinson disease (PD) with levodopa elevates homocysteine. The authors conducted a 6-week, multicenter, randomized, double-blind, placebo-controlled trial to test whether folate 1 mg/vitamin B(12) 500 microg or entacapone reduced serum homocysteine in 35 levodopa-treated PD patients. Levodopa initiation caused a small elevation in homocysteine. Vitamin therapy, but not entacapone, resulted in a decrease in homocysteine compared to placebo.

Topics: Aged; Antiparkinson Agents; Canada; Catechols; Double-Blind Method; Drug Combinations; Female; Folic Acid; Homocysteine; Humans; Hyperhomocysteinemia; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Placebo Effect; Treatment Outcome; United States; Vitamin B 12; Vitamins

Topics: Aged; Aged, 80 and over; Antiparkinson Agents; Carbidopa; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Cohort Studies; Drug Interactions; Drug Therapy, Combination; Enzyme Inhibitors; Female; Homocysteine; Humans; Hyperhomocysteinemia; Levodopa; Male; Middle Aged; Nitriles; Treatment Outcome

Levodopa (l-dopa) therapy in Parkinson's disease (PD) increases serum homocysteine levels because of its metabolism via catechol O-methyltransferase, which may lead to endothelial dysfunction.. We enrolled 40 PD patients treated with l-dopa, 33 PD patients treated with l-dopa/entacapone, 22 untreated PD and 30 controls, and compared the flow-mediated dilation in these subjects.. The flow-mediated dilation was significantly lower in PD patients with l-dopa (6.0 ± 1.8%) than in those with l-dopa/entacapone (7.2 ± 1.1%, P = 0.03), untreated PD patients (7.8 ± 1.2%, P < 0.05), and controls (8.5 ± 2.9%, P < 0.05). The homocysteine level was significantly higher in PD patients with l-dopa than in other groups. In a multivariate logistic regression model, the uppermost homocysteine quartile was an independent predictor of the lowest tertile of flow-mediated dilation (odds ratio, 6.33; 95% confidence interval, 1.61-26.65; P = 0.012).. Our findings indicate that endothelial dysfunction may be associated with chronic l-dopa treatment in patients with PD.

Topics: Aged; Antiparkinson Agents; Brachial Artery; Catechols; Dilatation; Endothelium; Female; Homocysteine; Humans; Hyperhomocysteinemia; Levodopa; Logistic Models; Male; Middle Aged; Nitriles; Parkinson Disease; Statistics, Nonparametric

Total plasma homocysteine (tHcy) may be a risk factor for vascular diseases and is associated with renal failure or deficiency of vitamin B12 or folate. Recently, elevated tHcy concentrations were observed in patients with Parkinson's disease (PD), particularly those under levodopa treatment. Our objective was to determine whether changes in tHcy are also found in patients with restless legs syndrome (RLS) in relation to levodopa treatment and whether folate and vitamins B6 and B12 play a role in RLS.. In a total of 228 subjects, tHcy and B vitamin status (vitamins B6 and B12, folate) were studied: 97 patients with idiopathic RLS (40 under levodopa therapy), 39 with PD (25 under levodopa therapy), and 92 healthy controls adjusted for age and gender.. No significant differences were observed in tHcy levels between RLS patients and controls or between the RLS groups without treatment or with levodopa or dopamine agonist treatment. Mean tHcy was significantly higher in PD patients (13.8 micromol/l) than in either RLS patients (11.7 micromol/l) or controls (11.0 micromol/l; p<0.001). There was an inverse association between tHcy and vitamin B12 in each group.. RLS and, in particular, levodopa treatment in RLS are not associated with hyperhomocysteinemia. Elevated tHcy could, however, be confirmed in PD patients.

Topics: Aged; Antiparkinson Agents; Catechols; Female; Folic Acid; Homocysteine; Humans; Hyperhomocysteinemia; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Reference Values; Restless Legs Syndrome; Vitamin B 12; Vitamin B 6

This study investigated whether brief exposure to nitrous oxide (N(2)O) exacerbates levodopa-induced hyperhomocysteinemia, and if co-treatment with folate or entacapone could reduce total plasma homocysteine (tHcy) levels.. MALE WISTAR RATS (N=9 PER GROUP) WERE RANDOMLY TREATED WITH VEHICLE/N(2)O (GROUP 1), levodopa/nitrogen (group 2), levodopa/N(2)O (group 3), levodopa/N(2)O+folate (group 4), or levodopa/N(2)O+entacapone (group 5). tHcy was measured at 12 min, 4, 8, and 12 h after anesthesia.. The combination of N(2)O-exposure and levodopa treatment significantly increased tHcy in rats. This hyperhomocysteinemia could be prevented by entacapone but not folate co-administration.

Topics: Analgesics, Non-Narcotic; Analysis of Variance; Animals; Catechols; Drug Interactions; Enzyme Inhibitors; Homocysteine; Hyperhomocysteinemia; Immunoassay; Levodopa; Male; Nitriles; Nitrous Oxide; Random Allocation; Rats; Rats, Wistar

Topics: Antiparkinson Agents; Carbon; Catechol O-Methyltransferase Inhibitors; Catechols; Folic Acid; Humans; Hyperhomocysteinemia; Levodopa; Nitriles; Parkinson Disease; Randomized Controlled Trials as Topic; S-Adenosylmethionine; Time Factors; Vitamin B 12; Vitamin B 6

Levodopa treatment has been shown to increase plasma homocysteine levels in Parkinson's disease (PD) patients and this may lead to an increased risk for coronary arterial diseases. Levodopa is metabolised via O-methylation by catechol-O-methyltransferase (COMT) using S-adenosyl-L-methionine (SAM) as the methyl donor, this leading to the subsequent formation of homocysteine. In this study, the effects of the COMT inhibitor, entacapone, on levodopa-induced hyperhomocysteinaemia were studied in rats. Using a single dose acute treatment paradigm, entacapone (10 or 30 mg/kg) prevented the levodopa (30 or 100 mg/kg) induced rise in plasma homocysteine levels in a dose-dependent manner. Five-day sub-chronic treatment with levodopa (3 x 100 mg/kg per day) resulted in a marked rise in plasma homocysteine levels when measured 2 hours post-treatment on Day 5. These levels fell but remained greater than baseline at 8 hours post-treatment on Day 5. Consistent with findings in the acute treatment test paradigm, the co-administration of entacapone (30 mg/kg) significantly (p<0.001) reduced levodopa-induced hyperhomocysteinaemia for up to 2 hours post-treatment on Day 5 of the sub-chronic study. These results suggest that entacapone may reduce levodopa-induced hyperhomocysteinaemia in PD patients.

Topics: Animals; Antiparkinson Agents; Catechol O-Methyltransferase Inhibitors; Catechols; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Homocysteine; Hyperhomocysteinemia; Levodopa; Male; Nitriles; Rats; Rats, Wistar

Hyperhomocysteinemia is not only a major risk factor for atherothrombotic disease, but is also strongly associated with an increased risk of dementia and cognitive impairment, both of which are common in the course of Parkinson's disease (PD). Previous work has found that levodopa increases plasma homocysteine concentrations. Animal studies have indicated that the catechol-O-methyltransferase (COMT) inhibitors can prevent levodopa-induced elevation of homocysteine concentrations by reducing the O-methylation of levodopa. The objective of our study was to assess the impact of entacapone, a COMT inhibitor, on plasma levels of homocysteine, serum folate, and vitamin B12 in levodopa-treated PD patients. Nineteen PD patients receiving only levodopa and 21 PD patients on a combination of levodopa and entacapone participated in the cross-sectional study. The control group consisted of 17 subjects on dopamine agonists. The mean plasma homocysteine concentration in the subjects on only levodopa was higher than that in the subjects on a combination of levodopa and entacapone (P=0.001) or in the control group (P=0.0001). Concentrations of serum vitamin B12 and serum folate were on average normal in all groups, but levodopa-treated subjects (with or without entacapone therapy) were more prone to have hypovitaminosis B12 (45%) than controls on dopamine agonists (6%). We suggest that the COMT inhibition may play a promising role in successfully controlling levodopa-induced hyperhomocysteinemia and in reducing the risk of pathologies probably linked to it. These preliminary findings and postulated hypotheses must now be confirmed in prospective studies.

Topics: Aged; Aged, 80 and over; Antiparkinson Agents; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Cross-Sectional Studies; Drug Therapy, Combination; Enzyme Inhibitors; Female; Folic Acid; Homocysteine; Humans; Hyperhomocysteinemia; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Vitamin B 12