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PubMed1999

The effect of tolcapone on the pharmacokinetics of benserazide.

This study investigated the potential interaction between tolcapone, a catechol-O-methyltransferase (COMT) inhibitor, and the decarboxylase inhibitor, benserazide. In an open-labelled six-week study, patients with Parkinson's disease (PD), treated with levodopa/benserazide, were given tolcapone at 200 mg t.i.d. Blood samples for analysis of benserazide, its main active metabolite, trihydroxybenzylhydrazine, levodopa and 3-O- methyldopa (3-OMD) were collected immediately before and repeatedly after the first drug intake of the day at baseline and after 1-2 and 6 weeks of treatment. Furthermore, animal experiments were performed to determine the levels of benserazide and trihydroxybenzylhydrazine at doses for which safety had previously been established. It was shown that tolcapone can cause an increase in benserazide plasma concentrations and that this effect is dependent on the benserazide dose. When tolcapone was combined with 25 mg benserazide the elevation was small. Although the increase was more pronounced when tolcapone was combined with 50 mg benserazide, the levels were still substantially lower than concentrations causing toxicity in animals. The safety margin derived from this study, together with the absence of any organic toxic effects in clinical trials, show that the observed interaction between tolcapone and benserazide does not represent a safety concern for PD patients treated with this combination.

Aged↗
PubMed1999

COMT inhibition by tolcapone further improves levodopa pharmacokinetics when combined with a dual-release formulation of levodopa/benserazide. A novel principle in the treatment of Parkinson's disease.

The objective of the study reported here was the investigation of the effect of catechol-O-methyl transferase (COMT) inhibition by tolcapone on the pharmacokinetics of levodopa and 3-O-methyldopa (3-OMD) after administration of a new dual-release formulation (dual-RF) of levodopa/benserazide (200/50). The study had a double-blind, placebo-controlled, randomized, crossover design and was conducted in 18 healthy young subjects. On the 2 treatment days, separated by a washout period of 7 days, the dual-RF was administered in combination (blinded) with tolcapone (200 mg) or placebo. Both treatment combinations were well tolerated. Tolcapone increased the bioavailability (AUC 0-infinity) and apparent elimination half-life (t(1/2)) of levodopa by 80 and 40%, respectively, compared to placebo. The maximal plasma concentration (Cmax) was slightly elevated by tolcapone. In the presence of tolcapone, formation of 3-OMD was substantially reduced. In conclusion, the effect of tolcapone on levodopa pharmacokinetics after administration of the dual-RF is similar to the one observed after immediate- and slow-RFs and leads to a marked improvement in levodopa pharmacokinetics and subsequently to an optimization of levodopa therapy.

Adolescent↗
PubMed2000

The specificity of glucuronidation of entacapone and tolcapone by recombinant human UDP-glucuronosyltransferases.

The COMT inhibitors entacapone and tolcapone are rapidly metabolized in vivo, mainly by glucuronidation. In this work, the main UGT isoforms responsible for their glucuronidation in vitro were characterized by using a subset of representative cloned and expressed human UGT isoforms. Entacapone in particular was seen to be an exceptionally good substrate for UGT1A9 with an even higher reaction velocity value at 500 microM substrate concentration compared with that of the commonly used substrate, propofol (1.3 and 0.78 nmol min(-1) mg(-1), respectively). Neither entacapone nor tolcapone was glucuronidated by UGT1A6. Tolcapone was not detectably glucuronidated by UGT1A1, and the rate of glucuronidation of entacapone was also low by this isoform. However, UGT1A1 was the only UGT capable of catalyzing the formation of two glucuronides of the catecholic entacapone. Both COMT inhibitors were glucuronidated at low rates by the representative members of the UGT2B family, UGT2B7 and UGT2B15. Michaelis-Menten parameters were determined for entacapone and tolcapone using recombinant human UGT isoforms and human liver microsomes to compare the kinetic properties of the two COMT inhibitors. The kinetic data illustrates that UGT1A9 exhibited a much greater rate of glucuronidation and a far lower K(m) value for both entacapone and tolcapone than UGT2B15 and UGT2B7 whose contribution is minor by comparison. Entacapone showed a 3 to 4 times higher V(max) value and a 4 to 6 times lower K(m) value compared with those of tolcapone both in UGT1A9 cell lysates and in human liver microsomes.

Animals↗
PubMedDate not supplied

[Microdialysis study of tolcapone effect during blockage of neuronal dopamine reuptake caused by GBR-12909].

In vivo brain functions analysis was conducted to assess the effect of tolcapone, a novel catechol-O-methyltransferase (COMT) inhibitor on extracellular levels of dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum of awake, freely moving eats during GBR 12909-induced blockade of DA uptake. Tolcapone administration (30 mg/kg, i.p.) failed to change the dopamine output but caused a marked and long-lasting decrease in the extracellular level of HVA and increase in that of DOPAC. In contrast, injection of the DA uptake inhibitor GBR 12909 directly into the striatum (5 microM) or i.p. (20 mg/kg) led to increase in the DA level but had no significant effect on the metabolites. Co-administration of tolcapone (30 mg/kg i.p.) and CBR 12909 (20 mg/kg) increased the DA level further, whereas the changes in HVA and DOPAC levels remained approximately the same as after injection of tolcapone alone. Behavioral observation showed GBR 12909-induced hyperactivity and stereotypy to be potentiated by tolcapone. These findings show that in the rat striatum under conditions of normal nerve activity DA uptake completely inhibits the increase in striatal DA neurotransmission induced by tolcapone (30 mg/kg i.p.) through COMT inhibition.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2000

Tolcapone and hepatotoxic effects. Tasmar Advisory Panel.

Four patients with Parkinson disease have recently been described in whom severe hepatic dysfunction developed in association with tolcapone therapy. These reports led to the introduction of a "black box" warning and more intensive monitoring requirements in the United States. A review of these cases and all clinical trials indicates that liver dysfunction did not develop in any patient who had received monitoring of liver function according to the original prescribing information. Virtually all instances of liver enzyme abnormality and clinical liver dysfunction occurred within 6 months of initiating treatment. To assess the current role of tolcapone therapy in Parkinson disease, a panel of neurologists and hepatologists was convened. Consensus was reached with respect to the following: (1) Tolcapone is an effective agent in the treatment of patients with fluctuating Parkinson disease. (2) The risk of developing irreversible liver injury is negligible with appropriate monitoring. (3) It may be possible to reduce the frequency of monitoring after 6 months of treatment. (4) The requirement that tolcapone be withdrawn if liver enzymes are elevated above the upper limit of normal on a single occasion is unnecessarily restrictive. It was concluded that tolcapone, when used as an adjunct to levodopa, is an effective anti-parkinsonian agent and that less frequent monitoring after 6 months, with an action limit of 2 to 3 times the upper limit of normal, is sufficient to ensure safety in patients who are deriving benefit from the drug.

Aged↗
PubMed1995

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

A double-blind, placebo-controlled, crossover trial of tolcapone (RO 40-7592), 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.

Aged↗
PubMed1995

Effects of tolcapone, a novel catechol-O-methyltransferase inhibitor, on striatal metabolism of L-dopa and dopamine in rats.

In vivo brain microdialysis was used to assess the effects of tolcapone, a novel central and peripheral inhibitor of catechol-O-methyltransferase on striatal 3,4-dihydroxyphenyl-L-alanine (L-dopa) and dopamine metabolism. The oral administration of 30 mg/kg of tolcapone failed to change dopamine output but elicited a marked and long-lasting decrease of the extracellular levels of homovanillic acid (HVA) and 3-methoxytyramine with a concomitant increase of 3,4-dihydroxyphenylacetic acid (DOPAC). The administration of L-dopa (20 and 60 mg/kg p.o.) + benserazide (15 mg/kg p.o.) resulted in dose-dependent increase of dialysate levels of L-dopa and 3-O-methyl-DOPA. Tolcapone (30 mg/kg p.o.), given as adjunct to both doses of L-dopa, markedly enhanced the elevation or extracellular L-dopa, while it completely prevented the formation of 3-O-methyl-DOPA. In another experiment, the administration of L-dopa + benserazide (30 + 15 mg/kg p.o.) resulted in increased extracellular levels of dopamine, DOPAC, HVA and 3-methoxytyramine. The co-administration of tolcapone (30 mg/kg p.o.) further increased dopamine and DOPAC levels, whereas HVA and 3-methoxytyramine effluxes were reduced. These findings support the notion that tolcapone has the ability to enhance striatal dopamine neurotransmission by increasing L-dopa bioavailability through peripheral and central inhibition of L-dopa O-methylation, as well as by blocking the central conversion of dopamine into 3-methoxytyramine.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1999

Effect of tolcapone, a catechol-O-methyltransferase inhibitor, on striatal dopaminergic transmission during blockade of dopamine uptake.

To examine the mechanisms of tolcapone in the central nervous system (CNS), we analyzed alterations in parameters of striatal dopamine transmission induced by this drug (30 mg/kg) co-administered with the selective dopamine uptake inhibitor, GBR 12909 (10 mg/kg). Using microdialysis in freely moving rats, it was determined that combined administration of tolcapone with GBR 12909 resulted in a further increase of dopamine levels over that obtained without the catechol-O-methyltransferase inhibitor, while tolcapone alone failed to change dopamine levels. Fast-scan cyclic voltammetric monitoring of electrically evoked dopamine did not show any changes in dopamine release after the combination of the drugs, but there was a pronounced decrease in the rate of dopamine clearance after GBR 12909 alone and when co-administered with tolcapone. These data indicate that in rat striatum, a tolcapone-induced increase in extracellular dopamine is not observed because of the presence of uptake. These results also support the hypothesis that under normal conditions, uptake, rather than metabolism, control extracellular levels of dopamine.

Animals↗
PubMed1997

Effect of tolcapone on plasma and striatal apomorphine disposition in rats.

The influence of tolcapone, an inhibitor of catechol-O-methyl transferase, was evaluated on the disposition of apomorphine, a dopamine agonist used to treat Parkinson's disease, to explain a previously observed increase of duration of the effect of apomorphine associated with tolcapone. Sampling was performed in rats before and at different times after administration of apomorphine and following that of tolcapone or saline. Both in plasma and striatum, times to reach maximal-concentration and maximal concentrations did not significantly differ between the two groups but the elimination half-life times and areas under the curve were significantly greater following tolcapone treatment than in the saline group. These results show that tolcapone can increase plasma apomorphine bioavailability by modifying its liver catabolism.

Animals↗
PubMed1999

Open study of the catechol-O-methyltransferase inhibitor tolcapone in major depressive disorder.

Tolcapone is a catechol-O-methyltransferase (COMT) inhibitor that has shown efficacy in the treatment of Parkinson's disease. The authors undertook the first study on the efficacy of this COMT inhibitor in the treatment of major depressive disorder (MDD). The authors also wanted to assess the effects of tolcapone on the choline and myoinositol resonances in the left caudate and dorsolateral frontal lobe through proton magnetic resonance spectroscopy and on whole blood levels of S-adenosyl-L-methionine (SAMe). The study enrolled 21 adults (10 men and 11 women; mean age, 42.6 +/- 9.6 years) with MDD, which was diagnosed using the Structured Clinical Interview for DSM-IV, and an initial score of > or = 16 on the 17-item Hamilton Rating Scale for Depression (HAM-D-17). Patients were then treated openly for 8 weeks with tolcapone 400 mg twice daily. Treatment efficacy was assessed with the HAM-D-17, the Clinical Global Impressions Severity (CGI-S) scale, and the Beck Depression Inventory (BDI). Among all subjects (N = 21), there were significant (p < .0001) decreases at endpoint in HAM-D-17 scores (from 19.4 +/- 2.9 to 10.7 +/- 5.5), CGI-S scores (from 3.9 +/- 0.6 to 2.4 +/- 1.1), and BDI scores (from 21.6 +/- 8.1 to 12.3 +/- 8.6). Eight patients (38%) dropped out before completing the 8-week open study because of diarrhea, elevated liver function tests, increased anxiety, and noncompliance. No significant effects were noted on choline and myoinositol resonance or on SAMe levels in whole blood before and after 2 weeks of tolcapone treatment. The preliminary results suggest that tolcapone may be a promising agent in the treatment of MDD. Furthermore, double-blind, placebo-controlled studies are necessary to confirm this impression.

Adult↗
PubMed2001

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.

Aged↗
PubMed1998

Pharmacokinetics, pharmacodynamics, and tolerability of tolcapone: a review of early studies in volunteers.

Tolcapone is a potent, reversible inhibitor of catechol O-methyltransferase (COMT) intended for use as an adjunct to levodopa therapy for Parkinson's disease (PD). Findings from the first pharmacokinetics/pharmacodynamics and tolerability studies of tolcapone in volunteers are reviewed. Following linear and dose-proportional pharmacokinetics, tolcapone is rapidly absorbed and eliminated after single- or multiple-dose (i.e., tid) administration. Onset of COMT inhibition is rapid, substantial, and reversible, and is not affected by the co-administration of levodopa/decarboxylase inhibitor (levodopa/DCI). When given together with levodopa/DCI, tolcapone increases the relative bioavailability and plasma elimination half-life of levodopa, without affecting its peak plasma concentration. This leads to more stable plasma levels of levodopa, and the formation of 3-O-methyldopa is effectively reduced. Tolcapone was well tolerated alone or in combination with levodopa/DCI, and the results indicated that the effective dose in patients with PD would be in the range of 50-400 mg tid.

Antiparkinson Agents↗
PubMed1999

Tolcapone, a selective catechol-O-methyltransferase inhibitor for treatment of Parkinson's disease.

Tolcapone is a selective peripheral and central catechol-O-methyltransferase (COMT) inhibitor recently approved as adjunctive therapy in patients with idiopathic Parkinson's disease who are already being treated with a levodopa-peripheral dopa decarboxylase inhibitor (DDI) combination. Tolcapone potentiates and prolongs the effect of levodopa in the central nervous system (CNS) by enhancing levodopa's delivery to the CNS and slowing dopamine's central metabolism. A short terminal disposition half-life of 2 hours mandates dosing 3 times/day. Dosage adjustment is generally unnecessary in the presence of mild to moderate renal and hepatic impairment. Coadministration of tolcapone with levodopa-DDI results in significant amelioration of the wearing-off and on-off phenomena and frequently allows significant levodopa dosage reduction. In patients with stable disease, tolcapone improves "on" time. As might be expected from its potentiation of levodopa effects, dopaminergic side effects are prominent with this agent. Although the main objective of drug treatment in Parkinson's disease remains clinical improvement with an optimum dose and frequency of levodopa administration, tolcapone may prove a useful adjunct to such therapy, especially in the presence of the wearing-off and on-off phenomena. The relative merits of this agent vis-a-vis dopamine receptor agonists are somewhat unclear at present. However, recent guidelines from the American Academy of Neurology suggest that a COMT inhibitor be added to levodopa-dopamine agonist therapy in patients with advanced disease.

Antiparkinson Agents↗
PubMed2000

The pharmacokinetic and clinical effects of tolcapone on a single dose of sublingual apomorphine in Parkinson's disease.

Apomorphine (APO) is a potent dopamine agonist that is partially metabolized by catachol-O-methyl transferase (COMT). Tolcapone was the first COMT inhibitor available for use as adjunctive therapy to levodopa in Parkinson's disease (PD). In order to determine whether this compound might increase the serum area under the curve (AUC) of APO and whether this results in any clinical benefit, we administered 200mg doses of tolcapone to five fluctuating PD patients taking an investigational sublingual APO preparation. Serial tapping speed and gait speed were assessed at 15min intervals over four hours, in conjunction with APO serum levels, following a single dose of APO, both before and five days after starting tolcapone (600mg/day). Serum APO levels tended to be higher (12.6%), and clinical measures suggested improvement during the APO "on" period after the addition of tolcapone (22.5% improvement in gait speed, and 7.6% improvement in tapping speed), but neither reached statistical significance. Further trials, involving larger samples are needed to clearly establish the pharmacokinetic and clinical effect of tolcapone in PD patients taking APO.

Journal Article↗
PubMed2000

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.

Adaptation, Psychological↗
PubMed2006

Tolcapone decreases plasma levels of S-adenosyl-L-homocysteine and homocysteine in treated Parkinson's disease patients.

BACKGROUND: Elevated plasma total homocysteine (tHcy) appeared in levodopa/dopadecarcoxylase inhibitor (DDI) treated patients with Parkinson's disease (PD). One therapeutic approach for tHcy reduction is vitamine supplementation, since folic acid and cobalamine catalyse and enhance metabolism of tHcy to methionine. A further therapeutic alternative is inhibition of catechol-O-methyltransfrase (COMT) on a regular basis, when levodopa/DDI treatment is performed. METHODS: We measured the concentrations of S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), tHcy, levodopa and 3-O-methyldopa in plasma of 13 levodopa treated PD patients before first drug intake at 0600 hours. Blood samples were taken before and after 2 days of additional application of the centrally acting catechol-O-methyltransferase inhibitor tolcapone 100 mg t.i.d. RESULTS: Plasma levels of SAH [day 1: 48.32+/-22.52, 23.92-98.25 (mean+/-SD, range; micromol/l); day 3: 37.72+/-15.84, 23.4-61.89; p = 0.01] and tHcy (day 1: 13.88+/-5.62, 7.63-24.81; day 3: 11.38+/-4.44, 5.98-20.45; p = 0.04) significantly reduced. Plasma levels of levodopa did not significantly (p = 0.17) increase, whereas 3-OMD concentrations significantly (p = 0.0002) reduced after additional tolcapone intake. There was no significant change of SAM plasma levels (p = 0.22). CONCLUSION: Our prospective trial shows, that COMT inhibition with tolcapone lowers tHcy synthesis. Tolcapone may also possess beside its proven, occasional, hepatotoxic potency also beneficial effects via decrease of SAH and tHcy. This may hypothetically reduce homocysteine mediated progress of neuronal degeneration and the risk for onset of dementia, vascular disease and polyneuropathy in levodopa treated PD patients in the long term.

Aged↗
PubMed2003

Modifications of plasma and platelet levels of L-DOPA and its direct metabolites during treatment with tolcapone or entacapone in patients with Parkinson's disease.

We compared--retrospectively--the effects of a 3-month therapy with catechol- O-methyltransferase (COMT) inhibitors tolcapone (100 mg, t.i.d.) and entacapone (200 mg, t.i.d.), on L-DOPA metabolism in two groups of parkinsonian patients with motor fluctuations. Plasma and platelets concentrations of L-DOPA and its direct metabolites, dopamine and 3- O-methyldopa (3-OMD), were measured before starting treatment, after two weeks and at the end of treatment. Patients treated with tolcapone showed significant increases in plasma and platelet L-DOPA levels and marked reduction of plasma and platelet 3-OMD levels, both at short- and long-term. Entacapone did not modify L-DOPA levels, while inducing a less marked reduction of plasma and platelet 3-OMD concentrations, with respect to tolcapone, at both time points. Both drugs were similarly effective in increasing plasma and platelet levels of dopamine. These results confirm the different profiles of activity of the two drugs, with tolcapone proving more effective on both the intra- and extra-cellular levels of L-DOPA and 3-OMD.

Age Factors↗
PubMed2000

Tolcapone increases maximum concentration of levodopa.

No significant increase of the maximum concentration (Cmax) of levodopa after addition of catechol-O-methyltransferase inhibitor tolcapone occurred in previous pharmacokinetic studies predominantly on healthy volunteers. We compared pharmacokinetics of levodopa in plasma before and after addition of tolcapone in 13 treated parkinsonian subjects under standardized conditions. We found a significant increase of Cmax of levodopa after the addition of tolcapone. This may represent one cause for the occurrence of dyskinesia previously early in the course of treatment with tolcapone.

Aged↗