Heart rate variability in Parkinson's disease patients treated with tolcapone

Following the introduction of tolcapone, a potent, reversible Catechol-O-methyltransferase (COMT) inhibitor, it has been possible to optimise the management of Parkinson's disease (PD) patients in chronic Levodopa (L-dopa) therapy. The interaction between tolcapone and the endogenous metabolism of catecholamines points to a possible influence on autonomic cardiovascular function.Cardiovascular reflexes have been analysed in a group of seven PD patients (four males, three females; mean age 69.7years, mean disease duration 14.1years) by means of the heart rate variability (HRV) method using a continuous 24-h ECG (ECGD), before and after six months of treatment with tolcapone (in addition to L-dopa).We have observed no statistically significant differences in HRV parameters, nor any changes in the incidence of hyperkinetic and hypokinetic arrhythmias, which suggest that autonomic cardiovascular function in PD patients is not influenced by six months of treatment with tolcapone.     

Safety and tolerability of adjunctive tolcapone treatment in patients with early Parkinson's disease

Objective

The safety and tolerability of adjunctive tolcapone initiated simultaneously with levodopa was evaluated with a focus on increases in liver transaminase and hepatotoxicity.

Methods

677 levodopa‐naïve patients with early stage Parkinson''s disease (PD) were randomised to receive placebo or tolcapone 100 mg three times daily, added to standard doses of levodopa plus carbidopa or benserazide.

Results

Increases in liver transaminase above the upper limit of normal (ULN) occurred in 69/342 (20.2%) and 92/335 (27.5%) patients in the placebo and tolcapone groups, respectively. Increases ⩾3 times the ULN occurred in 4/342 (1.2%) and 6/335 (1.8%) patients receiving placebo and tolcapone, respectively (p = 0.5). Liver transaminase values returned to normal in 65% of placebo and 80% of tolcapone treated patients. No instances of serious hepatotoxicity were seen. Diarrhoea was the most commonly reported AE—36/342 (11.0%) placebo v 98/335 (29.0%) tolcapone—and caused discontinuation in 9.9% of tolcapone treated patients. Overall, study discontinuation due to adverse effects was 2.9% in the placebo group and 17.3% in the tolcapone group.

Conclusions

Tolcapone seemed to be safe and was generally well tolerated as an adjunctive treatment in patients starting treatment with carbidopa/levodopa for symptomatic PD. Mild increases in transaminase levels—<3 times the ULN—occurred commonly in both placebo and tolcapone treated patients, whereas potentially serious increases of up to ⩾3 times the ULN were infrequent.     

Switch-over from tolcapone to entacapone in severe Parkinson's disease patients.

Forty patients affected by severe Parkinson's disease (PD) were treated with tolcapone as an adjunctive therapy to L-DOPA, for 3-7 months, until this drug was discontinued because of side-effects (2 diarrhoea, one of them with orthostatic hypotension, 2 increments of liver enzymes) or because of mandatory indications of the European drugs authority. All patients, after 3-6 months of L-DOPA therapy adjustments, received entacapone for 3 months again followed by withdrawal. L-DOPA daily dosage was significantly reduced by tolcapone and entacapone (p = 0.01 and 0.05). "On" time was increased by 15% during tolcapone treatment (p < 0.05), and by 8% during entacapone treatment. "Off" time was decreased by 16% during tolcapone and by 7% during entacapone treatment. Entacapone was withdrawn in the same patient who experienced diarrhoea and orthostatic hypotension during tolcapone because of recurrence of side-effects, in 6 patients because of increment of dyskinesias (with hallucinations) and in 1 patients because of rhythmic, jerking myoclonus.     

Long-term comparative experience with tolcapone and entacapone in advanced Parkinson's disease

The objective of this study was to compare the long-term tolerability and efficacy of tolcapone and entacapone in patients with fluctuating Parkinson's disease (PD). Tolcapone and entacapone are two currently available catechol- O -methyltransferase inhibitors that have demonstrated efficacy in the treatment of advanced PD. There are little published data on long-term experience and no direct comparisons. We compared the results of two separate, simultaneous, long-term open label extensions, one for tolcapone and the other for entacapone. The inclusion/exclusion criteria were similar. Data were collected prospectively at 6, 12, 24, and 36 months. Efficacy measures included the Unified Parkinson's Disease Rating Scale (UPDRS) total score, subscores, items 32 (duration of dyskinesia) and 39 (duration of "off" time), and levodopa dose. The two groups were compared using a Mann-Whitney U test for change from baseline and analysis of variance. Tolerability was defined as the ability of patients to maintain therapy and was compared using a Kaplan-Meier analysis. Eleven patients enrolled in the entacapone study and 14 in the tolcapone study. The tolcapone group had more severe disease with significantly higher UPDRS motor score, duration of "off," and levodopa dose requirement. Tolcapone was more effective in lowering UPDRS motor and complication subscores, duration of "off" time, and levodopa doses. UPDRS motor scores and change in levodopa dose in the tolcapone group remained below baseline level for 36 months; however, they were above baseline in the entacapone group from 6 months on. Tolerability was the same for both treatments. Tolcapone appears to have greater and longer efficacy with regard to motor symptoms, "off" time, and change in levodopa requirements than entacapone. These findings indicate that tolcapone continues to have a place in the treatment of advanced PD. However, the risks associated with this drug, particularly hepatic injury, and the requirement for rigorous blood monitoring, need to be considered when choosing an appropriate treatment for patients with advanced PD.     

Illness impact and adjustment to Parkinson's disease: before and after treatment with tolcapone.

Research on the impact of disease and treatment on health status and quality of life in patients with movement disorders is limited. We studied quality of life in 46 patients with Parkinson's disease (PD) to determine whether the impact of illness and psychosocial adjustment to illness were improved by 42 days of adjunctive therapy with tolcapone (50 mg, 200 mg, or 400 mg three times a day). This study was conducted in parallel with a double-blind, placebo-controlled, dose-response study of the safety and efficacy of tolcapone in combination with levodopa/carbidopa therapy. Only a subset of individuals from the larger study participated. In the quality of life study, illness impact and adjustment to illness were measured subjectively by the Sickness Impact Profile (SIP) and the Psychosocial Adjustment to Illness Scale-Self-Report (PAIS-SR). Patient ratings of total illness impact (p = 0.003), physical illness impact (p = 0.05), and psychosocial illness impact (p = 0.007) improved significantly in individuals receiving tolcapone compared with those receiving placebo. There was no statistically significant difference in adjustment to illness when the tolcapone and placebo groups were compared; however, 17 of 21 adjustment to illness indicators showed improvement.     

L-Dopa pharmacokinetics studied with microdialysis in patients with Parkinson's disease and a history of malignant melanoma

OBJECTIVES: The pharmacokinetics of free L-dopa in blood and tissue of five parkinsonian patients with malignant melanoma was studied with microdialysis. In one case the effect of L-dopa treatment on 5-S-cysteinyldopa and the melanoma was studied. Gastric emptying and its effects on free L-dopa in blood were also investigated in one of the patients. METHODS: Five patients were given 100 mg L-dopa with 25 mg benserazide. Blood and dialysates from the circulation and fatty tissue were collected for analysis. [13C]-Octanoic breath test was used for analyzing gastric half-emptying time. RESULTS: Four of the patients had similar pharmacokinetic patterns for L-dopa and a significant (P < 0.05) increase of serum 5-S-cysteinyldopa occurring 30 min after L-dopa intake. Delayed L-dopa peaks and slow gastric half-emptying time were found in 1 patient. A dose-dependent increase of 5-S-cysteinyldopa occurred but no melanoma metastases were seen during long-term L-dopa therapy. CONCLUSION: L-dopa therapy increases 5-S-cysteinyldopa levels but does not seem to cause progress of melanomas. Gastric emptying impacts L-dopa pharmacokinetics.     

Homocysteine levels after acute levodopa intake in patients with Parkinson's disease

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. © 2009 Movement Disorder Society     

L-Dopa medication remediates cognitive inflexibility,but increases impulsivity in patients with Parkinson's disease

In the current study we investigated the role of dopamine in attentional and socio-emotional functioning by examining effects of withdrawing dopaminergic medication in patients with Parkinson's disease (PD). Patients "on" medication exhibited abnormal betting strategies on a task of decision-making, reflecting impulsive behaviour and/or delay aversion, whilst the same patients "off" medication exhibited abnormally increased switch costs when switching between two tasks, reflecting attentional inflexibility. Hence, these data replicate and extend previous findings that dopaminergic medication improves or impairs cognitive performance depending on the nature of the task and the basal level of dopamine function in underlying cortico-striatal circuitry.     

Role of tolcapone in the treatment of Parkinson's disease

For decades, the cornerstone of treatment for Parkinson's disease (PD) has been levodopa, which provides a smooth clinical response early in the course of disease. However, many PD patients develop motor complications on long-term levodopa therapy. Catechol-O-methyltransferase (COMT) is a selective and widely distributed enzyme involved in the catabolism of levodopa. Tolcapone and entacapone are selective and potent COMT inhibitors that slow the metabolism of levodopa, thus prolonging its effects. While both drugs act peripherally, tolcapone also inhibits COMT in the CNS. Tolcapone has been shown to be an effective adjunct in the treatment of PD in Phase II and III clinical trials, improving motor fluctuations and reducing levodopa requirements. Rare reports of severe hepatotoxicity, however, limited tolcapone's implementation in the treatment of PD. A reappraisal of the data for tolcapone treatment in PD has found that this risk is very small if proper hepatic monitoring guidelines are followed. This article reviews the pharmacology and clinical data on tolcapone, with particular focus on drug safety and the future role of tolcapone therapy in the treatment of PD.     

Pharmacokinetics and pharmacodynamics in Japanese and Caucasian subjects after oral administration of dabigatran etexilate

Ethnic differences in drug disposition may potentially influence therapeutic response to dabigatran, a reversible direct thrombin inhibitor used for the prevention and/or treatment of various thromboembolic disorders. This analysis of data from 18 clinical studies in healthy volunteers and patients with non-valvular atrial fibrillation (AF) or undergoing knee or hip arthroplasty investigated whether there were any clinically relevant differences in the pharmacokinetics and pharmacodynamics of dabigatran, the active form of dabigatran etexilate, between Japanese and Caucasian subjects. In pooled data from 14 phase I trials, total exposure (i.e. area under the plasma concentration-time curve [AUC]) after administration of dabigatran 150 mg once or twice-daily was on average 20% higher in Japanese than Caucasian subjects (median [10th to 90th percentile] 1,110 [644-1,824] vs. 924 [420-1,654] ng·h/ml) although the difference between the groups was not significant. Within-trial comparisons in subjects treated with dabigatran 150 mg twice-daily showed that AUC and maximum plasma concentration differed by less than 10% between the two groups. In patients with AF, trough concentrations after administration of 150 mg twice-daily were similar in Japanese and Caucasian subjects (80.1 [34.5-193.8] vs. 71.0 [34.0-190] ng/ml). Various factors, including body weight and renal clearance, may explain these observed pharmacokinetic differences. The relationship between plasma concentration and coagulation markers was similar and indicative of no difference in the exposure-pharmacodynamic response between these two groups. In conclusion, the results of this analysis show that the pharmacokinetics and pharmacodynamics of dabigatran are similar in Japanese and Caucasian subjects and suggest that there is no need for dose adjustment of dabigatran in Japanese subjects.     

Effect of acute L-Dopa pretreatment on apomorphine-induced rotational behavior in a rat model of Parkinson's disease

Currently, reduction of apomorphine-induced rotational behavior in the 6-hydroxydopamine (6-OHDA) lesioned rat is the most utilized drug-induced paradigm for assessing functional efficacy in a rat model of Parkinson's disease (PD). Any clinically predictive animal model of PD should include a positive response to l-dopa, the standard pharmacotherapy for PD. However, the acute interaction between L-dopa and apomorphine has never been studied to determine if L-dopa pretreatment could reduce apomorphine-induced rotational behavior in a 6-OHDA lesioned rat. The present study was designed to explore whether, indeed, pretreatment with subrotational doses of L-dopa could inhibit apomorphine-induced rotations. The data indicate that L-dopa significantly reduced apomorphine-induced rotational behavior only at one dose (5.0 mg/kg) for 12 min. Based on these and other data, it is concluded that although the apomorphine-induced rotational paradigm may continue to be utilized as one additional indicator of efficacy in the 6-OHDA rat model of PD, it is not in itself a completely valid functional assay.     

Effects of tolcapone in Parkinson's patients taking L-dihydroxyphenylalanine/carbidopa and selegiline

A double-blind, placebo-controlled, crossover trial of tolcapone (RO 407592), a potent reversible inhibitor of catechol-O-methyltransferase (COMT), was performed in 10 Parkinson's disease (PD) patients to determine single-dose safety and efficacy. All subjects were chronically treated with stable doses of selegiline and L -dihydroxyphenylalanine (L -DOPA)/carbidopa. Tolcapone was administered in four single ascending doses (50-800 mg) randomly paired with placebo. Motor ratings were performed every 30 min for 6 h. At higher doses (400 mg and 800 mg), tolcapone prolonged the antiparkinson response of L -DOPA. Nausea was the most common adverse effect of the tolcapone—L -DOPA/carbidopa—selegiline combination. Adverse cardiovascular effects were not seen. The acute inhibition of amino acid decarboxylase, monoamine oxidase-B, and COMT is well tolerated and prolongs the L -DOPA response in PD patients. Tolcapone may be a safe and useful adjunct to L -DOPA/carbidopa in PD patients taking selegiline.     

Effects of tolcapone, a catechol-O-methyltransferase inhibitor, on motor symptoms and pharmacokinetics of levodopa in patients with Parkinson's disease

Summary The effects of tolcapone, a catechol-O-methyltransferase inhibitor, on the bioavailability and efficacy of levodopa were evaluated in 12 patients with Parkinson's disease (PD), 8 of whom showed signs of daily motor fluctuations (wearing-off phenomenon). Motor disabilities were assessed in 12 patients at 7 time points before and after the chronic administration of tolcapone using the Unified Parkinson's Disease Rating Scale (UPDRS). The UPDRS score was improved at all points of determination. Eight patients with wearing-off phenomenon on levodopa showed symptomatic improvement on the combination. The area under the curve (AUC) for levodopa increased by 34% (p=0.0059) after the administration of tolcapone. The elimination half-life (T1/2) of levodopa was significantly prolonged by 81% (p=0.0001) after the treatment. The AUC of 3-O-methyldopa, a metabolite of levodopa, was decreased by 79% (p=0.0001) and the Cmax (maximum concentration) was also decreased by 80% after the administration (p=0.0001) of tolcapone. The combination of tolcapone and levodopa was well tolerated. Our findings suggest that tolcapone improves the pharmacokinetics of levodopa in plasma and motor symptoms of fluctuating PD patients. It is suggested that tolcapone may be a useful drug adjunct to levodopa in treating patients with PD with wearing-off phenomena.     

Evidence-based efficacy comparison of tolcapone and entacapone as adjunctive therapy in Parkinson's disease

The relative efficacy has not been adequately established for the two catechol- O -methyltransferase (COMT) inhibitors that are currently available for adjunctive therapy in Parkinson's disease; tolcapone and entacapone. A recent Cochrane meta -analysis of 14 studies in 2566 patients, conducted to assess the efficacy and safety of tolcapone and entacapone, found both to be statistically superior to placebo in increasing ON time and decreasing OFF time. The meta -analysis also showed that the weighted mean difference from baseline to endpoint in tolcapone-treated patients was twice that in entacapone-treated patients for both placebo-corrected ON time and OFF time. Withdrawal rates were generally lower for tolcapone. Two additional studies have examined the switch between tolcapone and entacapone. In 40 Parkinson's disease patients with fluctuations who were switched from tolcapone to entacapone, improvements in ON time and reductions in OFF time were approximately twice the magnitude for tolcapone than for entacapone. In a second study examining the switch from entacapone to tolcapone, the results for several exploratory variables also suggested that tolcapone has greater efficacy than entacapone. These findings indicate that tolcapone should be considered in all patients with entacapone-refractory motor fluctuations.