Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

BIA 3-202 is a novel catechol-O-methyltransferase (COMT) inhibitor being developed for use as a levodopa-sparing agent in Parkinson's disease. This study investigated the effect of four single oral doses of BIA 3-202 (50 mg, 100 mg, 200 mg, and 400 mg) compared with placebo on plasma concentrations of levodopa and its metabolite 3- O-methyl-levodopa (3-OMD) and on inhibition of erythrocyte COMT in healthy subjects receiving 100 mg of levodopa and 25 mg of benserazide (Madopar 125). This was a single-centre, double-blind, placebo-controlled, randomised, crossover study with five single-dose treatment periods. The washout period between doses was 2 weeks. On each treatment period, a different dose of BIA 3-202 or placebo was administered concomitantly with Madopar 125. Tolerability was assessed by recording adverse events, vital signs, continuous electrocardiogram and clinical laboratory parameters. In the study, 18 subjects (12 male and 6 female) participated. The drug combination was well tolerated. All doses of BIA 3-202 significantly increased the area under the concentration-time curve (AUC) versus placebo, ranging from 39% (95% confidence intervals, 1.06-1.69) with 50 mg to 80% (95% confidence intervals, 1.42-2.22) with 400 mg. No significant change in mean maximum plasma concentrations (C(max)) of levodopa was found. Mean C(max) and AUC of 3-OMD significantly decreased for all doses tested. BIA 3-202 caused a rapid and reversible inhibition of S-COMT activity, ranging from 57% (50 mg) to 84% (400 mg). In conclusion, the novel COMT inhibitor BIA 3-202 was well tolerated and significantly increased the bioavailability of levodopa and reduced the formation of 3-OMD when administered with standard release levodopa/benserazide.
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PMID:Pharmacokinetic-pharmacodynamic interaction between BIA 3-202, a novel COMT inhibitor, and levodopa/benserazide. 1451 7

Entacapone is a catechol-O-methyltransferase (COMT) inhibitor used as an adjunct to levodopa/dopa decarboxylase inhibitors in the treatment of Parkinson's disease. Entacapone increases the bioavailability and reduces the daily variation of plasma levodopa when administered with standard levodopa preparations. These parameters were studied when entacapone was administered with a controlled-release levodopa preparation after repeated administrations throughout the day in 16 healthy male volunteers. On 2 test days, 200 mg entacapone or placebo was administered 4 times during the day at 4-hour intervals concomitantly with a single dose of controlled-release levodopa/carbidopa 100 mg/25 mg (Sinemet CR). Plasma levodopa, 3-O-methyldopa (3-OMD), and carbidopa concentrations were measured before intake of the medication and then every 30 minutes for 16 hours (until midnight), and less frequently up to 24 hours after the first levodopa dose. The minimum, maximum, and average concentration of levodopa; the daily variation of levodopa concentration; and the area under the time concentration curve (AUC) were calculated. The mean (+/-SD) plasma levodopa AUC was 39% (P = 0.0001) higher with entacapone (11,802 +/- 1454 ng/hour/mL) compared with placebo (8465 +/- 927 ng/hour/mL). The daily variation of plasma levodopa was reduced by about 25% with entacapone (P < 0.01). Entacapone significantly reduced plasma 3-OMD concentration by about 50% (P = 0.0001), indicating marked COMT inhibiting activity. There were no differences in plasma carbidopa concentrations. Entacapone significantly increased the bioavailability of levodopa and reduced its daily variation when administered concomitantly with a controlled-release levodopa preparation.
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PMID:Entacapone increases levodopa exposure and reduces plasma levodopa variability when used with Sinemet CR. 1596 9

Addition of the catechol-O-methyltransferase (COMT) inhibitor entacapone (EN) prolongs plasma metabolism of levodopa (LD). Objectives were to determine the clinical response after EN addition and the plasma degradation of LD and 3-O-methyldopa [3-OMD]. Not optimum treated hospitalised patients with Parkinson's disease received the same LD dosage on the first day only with carbidopa (CD) and on the second day with CD and EN (t.i.d.) within a standardised setting. We scored motor symptoms and measured LD- and 3-OMD levels on both days at fixed moments. Motor impairment significant better improved probably due to significant higher maximum concentrations [C(max)] and computed area under the curve values of LD levels during the LD/CD/EN condition. Time to C(max) of LD was significantly delayed after the first two LD/CD/EN intakes. An impact of EN on 3-OMD levels appeared. A possibly augmented LD absorption and a prolonged LD metabolism after EN supplementation may contribute to a more continuous LD delivery to the brain.
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PMID:Pharmacokinetic behaviour of levodopa and 3-O-methyldopa after repeat administration of levodopa/carbidopa with and without entacapone in patients with Parkinson's disease. 1660 2

Levodopa (LD) application improves motor symptoms in patients with Parkinson's disease (PD) patients. Little is known on further effects of LD, which induced lower plasma levels of cortisol and lower serotonergic activity in certain brain areas of fish. Objectives of this trial were to analyse levels of cortisol, LD and 3-O-methyldopa (3-OMD) after administration of LD/benserazide in long term treated PD patients. 12 PD patients, taken off their regular treatment for at least 12 hours, received soluble 200 mg LD/50 mg benserazide under stress free conditions. Motor symptoms improved, LD and 3-OMD levels increased, whereas cortisol concentrations started to decrease significantly 30 minutes after LD intake. This reduced cortisol release may result from an overflow of exogenous LD in the brainstem. This hypothetically causes an reduced 5-HT content in neurons projecting to the hypothalamic structures, which are involved in the partial 5-HT dependent central regulation of peripheral cortisol release.
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PMID:Acute levodopa administration reduces cortisol release in patients with Parkinson's disease. 1693 91

The interval of line tracing performance is more associated to basal ganglia function due to the dependence on bradykinesia and rigidity. The other component of this task, the precision of execution of complex movement sequences, is more related to attention. We compared the motor response after once dosing of 200 mg retarded release LD (levodopa)/CD (carbidopa) and of 150 mg LD/CD/EN (entacapone) by rating of motor symptoms, by measurement of LD- and 3-O-methyldopa (3-OMD) plasma concentrations and by the outcomes of a line tracing task. Thirteen treated patients with Parkinson's disease (PD) took one of the two tested LD formulations on two consecutive days under randomised, double blind, identical standardised conditions. No significant differences appeared regarding rated motor response and LD plasma concentrations, but 3-OMD only significantly went up after LD/CD intake. LD/CD/EN was superior to LD/CD regarding the attention related components of line tracing probably due to a hypothetically increased dopamine occurrence at the prefrontal cortex, which guides human behaviour.
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PMID:Comparison of 200 mg retarded release levodopa/carbidopa - with 150 mg levodopa/carbidopa/entacapone application: pharmacokinetics and efficacy in patients with Parkinson's disease. 1756 55

Long-term treatment of L-dopa for Parkinson's disease (PD) patients induces adverse effects, including dyskinesia, on-off and wearing-off symptoms. However, the cause of these side effects has not been established to date. In the present study, therefore, 3-O-methyldopa (3-OMD), which is a major metabolite of L-dopa, was tested to determine whether it plays a role in the aforementioned adverse effects. The effects of 3-OMD on the dopaminergic nervous system in the brain were investigated, by examining behavioral, biochemical, and cellular changes in male Sprague-Dawley rats and catecholamine-producing PC12 neuronal cells. The results revealed that the intracerebroventricular (icv) injection of 1 micromol of 3-OMD impaired locomotor activities by decreasing movement time (MT), total distance (TD), and the number of movement (NM) by 70, 74 and 61%, respectively. The biochemical analysis results showed that a single administration of 1 micromole of 3-OMD decreased the dopamine turnover rate (DOPAC/DA) by 40.0% in the rat striatum. 3-OMD inhibited dopamine transporter and uptake in rat brain striatal membranes and PC12 cells. The subacute administration of 3-OMD (5 days, icv) also significantly impaired the locomotor activities and catecholamine levels. 3-OMD induced cytotoxic effects via oxidative stress and decreased mitochondrial membrane potential in PC12 cells, indicating that 3-OMD can damage neuronal cells. Furthermore, 3-OMD potentiated L-dopa toxicity and these toxic effects induced by both 3-OMD and L-dopa were blocked by vitamin E (alpha-tocopherol) in PC12 cells, indicating that 3-OMD may increase the toxic effects of L-dopa to some extent by oxidative stress. Therefore, the present study reveals that 3-OMD accumulation from long-term L-dopa treatment may be involved in the adverse effects of L-dopa therapy. Moreover, L-dopa treatment might accelerate the progression of PD, at least in part, by 3-OMD.
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PMID:The role of 3-O-methyldopa in the side effects of L-dopa. 1771 53

A matter of debate is the impact of levodopa (LD) application in patients with Parkinson disease (PD) on altered force development and coordination, which are also influenced by the strength of muscles used. The objectives were to compare the motor response, the development of grip strength, and the pharmacokinetic behavior of LD and its main peripheral metabolite 3-O-methyldopa (3-OMD) after intake of 200-mg retarded-release levodopa/carbidopa (LD/CD) and of 150-mg LD/CD/entacapone (LD/CD/EN). Twelve patients with PD received both LD formulations within a standardized setting under double-blind conditions with a crossover design 1 day after the other. Motor symptoms significantly improved, LD plasma concentrations went up, and grip strength increased after both LD/CD and LD/CD/EN administration. There were no significant differences between both conditions with regard to motor response and LD pharmacokinetics. The 3-OMD levels were significantly lower during catechol-O-methyltransferase (COMT) inhibition with entacapone. The LD/CD/EN compound was superior over the retarded-release LD formulation, indicating the impact of LD on grip force. This may be caused by the interference of 3-OMD with the blood-brain barrier transport of LD; therefore, LD delivery is greater during the LD/CD/EN condition. Because the rating scale used does not consider the grip strength, this effect of better blood barrier transport of LD was not reflected. Another hypothesis may be that more acidic metabolites appear during peripheral LD metabolism by means of COMT, whereas COMT inhibition is accompanied by more basic LD metabolites (ie, the tyrosine aminotransferase-dependent substrates dihydroxyphenylpyruvate acetate and trihydroxyphenylacetate). This antiacid scenario may support a better muscle function with a positive impact on muscle excitability and contractibility.
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PMID:Catechol-O-methyltransferase inhibition improves levodopa-associated strength increase in patients with Parkinson disease. 1852 Sep 80

Levodopa (L-dopa) administered with a dopadecarboxylase inhibitor (DDI) increases homocysteine plasma levels. This may support the onset of atherosclerosis-related disorders and neuropsychiatric complications in patients with Parkinson's disease (PD). This homocysteine elevation is considered as long-term effect of chronic L-dopa/DDI treatment. Little is known about the acute effects of L-dopa/DDI intake on homocysteine generation. The objective of this trial was to investigate the relations between L-dopa and homocysteine after acute L-dopa/DDI administration in PD patients with different L-dopa metabolism. Thirty PD patients were divided into groups with superior (I) and less (II) L-dopa absorption after standardized intake of 125 mg L-dopa/benserazide with determination of L-dopa, 3-O-methyl-dopa (3-OMD) and homocysteine in plasma at baseline, 30, 60, and 90 minutes. There was a homocysteine increase in Group I (F = 5; P = 0.005) and a moderate decrease in Group II (F = 4.27; P = 0.01). A rise of 3-OMD (F = 10.51; P < 0.0001) appeared in Group I, but not in Group II (F = 0.91; P = 0.44), accordingly L-dopa accumulation was better in Group I than in Group II. Thus, in conclusion, L-dopa metabolism is an important component for homocysteine elevation after one time L-dopa/DDI administration in PD patients.
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PMID:Homocysteine levels after acute levodopa intake in patients with Parkinson's disease. 1942 84

Chronic levodopa (LD)/dopadecarboxylase inhibitor (DDI) increases homocysteine generation as side reaction of O-methylation. Aim was to investigate the impact of the peripheral COMT inhibitor entacapone (EN) on plasma concentrations of homocysteine, LD and 3-O-methyl-dopa (3-OMD). Patients with Parkinson's disease (PD) received on two consecutive days in a standardised fashion one single dose of 200 mg retarded release LD/carbidopa (CD) or of 150 mg LD/CD/EN, since both were shown to have simultaneous pharmacokinetic LD behaviour. Homocysteine increased after retarded release LD/CD application, but not following LD/CD/EN intake. Homocysteine was lower during the LD/CD/EN condition 80 min after baseline when compared with its levels after LD/CD administration. LD levels simultaneously rose on both days. 3-OMD concentrations did not change. Acute LD/CD application caused a rise of homocysteine levels, which was prevented by LD/CD/EN intake. Therefore, peripheral COMT inhibition may have a beneficial effect on putative, controversially debated components of homocysteine-related progression of PD.
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PMID:Peripheral COMT inhibition prevents levodopa associated homocysteine increase. 1965 87

Temporal variation in the motor function of Parkinson's disease (PD) patients suggests the potential importance of a chronobiological and chronopharmacological approach in its clinical management. We previously documented the effects of striatal injection of 6-OHDA (as an animal model of PD) on the circadian rhythms of temperature (T), heart rate (HR), and locomotor activity (A). The present work assessed the possible influence of L-Dopa on these same rhythms in the 6-OHDA animal model of PD. The study began after a four-week recovery period following surgical implantation of telemetric devices to monitor the study variables and/or anaesthesia. The study was divided into an initial one-week control period (W1) for baseline measurement of T, HR, and A rhythms. Thereafter, stereotaxic 6-OHDA lesioning was done. and a second monitoring for two weeks followed (W2, W3). Rats were then randomly divided into two groups: eight control rats received, via a mini-osmotic pump implanted subcutaneously, the excipient saline; the other eight rats received L-Dopa (100 mg/kg SC/day). After a seven-day period (W4), the pumps were removed and the T, HR, and A rhythms were monitored for two weeks (W5 and W6). To control for 6-OHDA striatal dopamine-induced depletion, 12 other rats were injected by identical methods (eight rats with 6-OHDA and four controls with saline) and sacrificed at W1, W3, and W5 for dopamine striatal content determination. To verify the delivery of levodopa from the osmotic pumps, plasma levels of levodopa and its main metabolites 3-OMD, DOPAC, and HVA were determined on separate group of rats receiving the drug under the same experimental conditions (osmotic pumps delivering continuously 10 microl/h for seven days, 100 mg/kg/subcutaneously). Our results agree with previously reported rhythmic changes induced by 6-OHDA--loss of circadian rhythmicity or changes in the main parameters of the registered rhythms. When circadian rhythmicity was abolished, L-Dopa treatment improved or accelerated recovery of the circadian rhythms, the effect being more pronounced for the HR rhythm. When circadian rhythms were not abolished but perturbed, L-Dopa treatment did not improve the 6-OHDA-induced changes in the T and A mesor (24 h mean level), while a significant effect was observed for HR. It appears that constant-rate L-Dopa infusion is unable to totally balance dopamine depletion; taking into account the circadian pattern of many structures implicated in drug effect, a sinusoidal delivery of L-Dopa must be evaluated in future experiments.
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PMID:Effects of L-Dopa on circadian rhythms of 6-OHDA striatal lesioned rats: a radiotelemetric study. 2037 Apr 68


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