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At least 19 recordsLinked to original sources

PubMed1998

A pilot evaluation of the tolerability, safety, and efficacy of tolcapone alone and in combination with oral selegiline in untreated Parkinson's disease patients. Tolcapone De Novo Study Group.

Tolcapone is a potent, reversible catechol-O-methyltransferase (COMT) inhibitor with both peripheral and central activity. It has been demonstrated to improve motor function and allow levodopa dose reductions in Parkinson's disease (PD) patients who are experiencing either a stable response or motor fluctuations while on levodopa/dopa decarboxylase inhibitor therapy. Because striatal dopamine is metabolized by COMT and monoamine oxidase (MAO), central COMT inhibition alone or in combination with MAO inhibition might provide symptomatic benefit for patients not receiving levodopa. We conducted a pilot study to evaluate the tolerability, safety, and efficacy of tolcapone alone and in combination with oral selegiline in early untreated PD patients. Patients were randomized to receive 200 mg tolcapone three times a day or placebo for the 8 weeks of the study. Open-label oral selegiline (5 mg in the morning and midday) was administered to all patients during the second 4 weeks of the study. There was no difference between treatment groups according to the investigator's assessment of tolerability at week 4. Ninety-five percent of tolcapone-treated patients and 98% of placebo-treated patients experienced excellent or good tolerability during the first 4 weeks (95% confidence interval [CI]: -10.3, 5.7; p = 0.57). A decrease in tolerability occurred in the tolcapone group during the second 4 weeks of the study following the addition of selegiline. The most commonly reported side effects were diarrhea (31% tolcapone, 7% placebo), nausea (21% tolcapone, 2% placebo), urine discoloration (12% tolcapone, 0% placebo), dizziness (12% tolcapone, 5% placebo), headaches (12% tolcapone, 10% placebo), and abdominal pain (10% tolcapone, 5% placebo). We did not identify symptomatic benefit associated with tolcapone alone or in combination with oral selegiline in this group of otherwise untreated PD patients.

Administration, Oral↗

PubMed1997

Tolcapone added to levodopa in stable parkinsonian patients: a double-blind placebo-controlled study. Tolcapone in Parkinson's Disease Study Group II (TIPS II).

The primary objective of this study was to assess the effect of tolcapone on levodopa dosage in parkinsonian patients whose "wearing-off" phenomenon has been controlled with more frequent levodopa dosage. After a 1-week placebo run-in, 97 patients were assigned randomly to receive placebo or tolcapone 200 or 400 mg three times daily (t.i.d.). Levodopa dosage was reduced by -35% on day 1 of study and subsequently retitrated as required. After 6 weeks, the tolcapone groups crossed over to receive the other dose for a further 3 weeks for exploratory purposes. Both tolcapone groups had greater reductions in levodopa dosage than the placebo group at week 6 (not statistically different). The 200-mg t.i.d. group showed greatest improvement in estimated mean scores for all efficacy parameters (p < 0.05 versus placebo for change in Unified Parkinson's Disease Rating Scale Subscale II). Fewer dopaminergic and nondopaminergic adverse events were associated with tolcapone 200 mg t.i.d. than with tolcapone 400 mg t.i.d. The most frequently reported dopaminergic adverse events were nausea, cramps, dyskinesia, and dystonia. The most frequently reported unanticipated adverse event was diarrhea. Tolcapone 200 mg t.i.d. may provide additional benefit to patients with moderately advanced Parkinson's disease with treated "wearing-off" phenomenon.

Activities of Daily Living↗

PubMed2003

In vitro metabolism of tolcapone to reactive intermediates: relevance to tolcapone liver toxicity.

Tolcapone is a catechol-O-methyltransferase (COMT) inhibitor used for control of motor fluctuations in Parkinson's disease (PD). Since its entry onto the market in 1998, tolcapone has been associated with numerous cases of hepatotoxicity, including three cases of fatal fulminant hepatic failure. The cause of this toxicity is not known; however, it does not occur with the use of the structurally similar drug entacapone. It is known that tolcapone is metabolized to amine (M1) and acetylamine (M2) metabolites in humans, but that the analogous metabolites were not detected in a limited human study of entacapone metabolism. We hypothesized that one or both of these tolcapone metabolites could be oxidized to reactive species and that these reactive metabolites might play a role in tolcapone-induced hepatocellular injury. To investigate this possibility, we examined the ability of M1 and M2 to undergo in vitro bioactivation by electrochemical and enzymatic methods. Electrochemical experiments revealed that M1 and M2 are more easily oxidized than the parent compound, in the order M1 > M2 > tolcapone. There was a general correlation between oxidation potential and the half-lives of the compounds in the presence of two oxidizing systems, horseradish peroxidase and myeloperoxidase. These enzymes catalyzed the oxidation of M1 and M2 to reactive species that could be trapped with glutathione (GSH) to form metabolite adducts (C1 and C2). Each metabolite was found to only form one GSH conjugate, and the structures were tentatively identified using LC-MS/MS. Following incubation of M1 and M2 with human liver microsomes in the presence of GSH, the same adducts were observed, and their structures were confirmed using LC-MS/MS and (1)H NMR. Experiments with chemical P450 inhibitors and cDNA-expressed P450 enzymes revealed that this oxidation is catalyzed by several P450s, and that P450 2E1 and 1A2 play the primary role in the formation of C1 while P450 1A2 is most important for the production of C2. Taken together, these data provide evidence that tolcapone-induced hepatotoxicity may be mediated through the oxidation of the known urinary metabolites M1 and M2 to reactive intermediates. These reactive species may form covalent adducts to hepatic proteins, resulting in damage to liver tissues, although this supposition was not investigated in this study.

Acetylation↗

PubMed1998

Randomized, placebo-controlled study of tolcapone in patients with fluctuating Parkinson disease treated with levodopa-carbidopa. Tolcapone Fluctuator Study Group III.

OBJECTIVE: To assess the efficacy and tolerability of the catechol-O-methyltransferase inhibitor tolcapone in reducing "off/on" fluctuations in levodopa-treated parkinsonian patients. DESIGN: A randomized, double-blind, placebo-controlled, parallel-group study. SETTING: Fifteen Parkinson disease clinics. PATIENTS: Two hundred fifteen referred outpatients with Parkinson disease who showed predictable end-of-dose motor fluctuations that were not controlled by a stable levodopa-carbidopa (Sinemet) regimen of at least 4 weeks' duration. INTERVENTIONS: In addition to their usual levodopa-carbidopa regimen, patients received placebo or tolcapone, 100 or 200 mg, 3 times daily orally for 6 weeks. PRIMARY OUTCOME MEASURE: Change in daily off/on time. RESULTS: Tolcapone, 100 and 200 mg 3 times daily, reduced off time by 2.0 and 2.5 hours per day, respectively, and increased on time by 2.1 and 2.3 hours per day, respectively (P<.001 vs placebo). Investigators' global measures of disease severity indicated that significantly more tolcapone-treated patients had reduced wearing off and symptom severity (P<.001 vs placebo). No significant change in quality-of-life measures occurred. Clinical improvements occurred despite a reduction in total daily levodopa dose of 185.5 mg (23%) in the tolcapone, 100 mg 3 times daily, group and 251.5 mg (29%) in the 200 mg 3 times daily group. Principal adverse events (mainly dyskinesia and nausea) were levodopa related, were not treatment limiting, and were seldom reported as reasons for withdrawal. The frequency of withdrawals because of adverse events was similar in all groups (3% to 7%). CONCLUSIONS: Tolcapone was well tolerated and substantially increased on time and reduced off time in patients with fluctuating Parkinson disease. Additionally, levodopa requirements were significantly decreased.

Aged↗

PubMed1997

Tolcapone in stable Parkinson's disease: efficacy and safety of long-term treatment. The Tolcapone Stable Study Group.

In this double-blind, placebo-controlled trial, we investigated the effect of the catechol-O-methyltransferase inhibitor tolcapone 100 or 200 mg three times daily on activities of daily living and motor function in 298 patients with parkinsonism receiving levodopa but without motor fluctuations. At 6 months, both dosages of tolcapone produced significant reductions in the Unified Parkinson's Disease Rating Scale scores for activities of daily living (Subscale II) and motor function (Subscale III) and in the total score for Subscales I to III. These improvements were maintained up to the 12-month assessment. At 6 months, both tolcapone groups had changes in levodopa dosage that were significantly different from placebo: the tolcapone groups had decreases in mean total daily dose of levodopa, whereas the placebo group had a mean increase. Tolcapone was well tolerated. The principal adverse events were levodopa-related, but these were generally mild or moderate. Diarrhea was the most frequent nondopaminergic adverse event. Tolcapone appears to be beneficial in the treatment of patients with parkinsonism who have not yet developed motor fluctuations.

Activities of Daily Living↗

PubMed1998

Tolcapone in stable Parkinson's disease: efficacy and safety of long-term treatment. Tolcapone Stable Study Group.

Aged↗

PubMed1999

Efficacy and tolerability of tolcapone compared with bromocriptine in levodopa-treated parkinsonian patients. Tolcapone Study Group.

The catechol-O-methyltransferase inhibitor tolcapone was compared with the dopamine agonist bromocriptine in an open-label, randomized trial involving 146 levodopa-treated parkinsonian patients with end-of-dose deterioration of efficacy. Tolcapone was given at a dosage of 200 mg three times daily; bromocriptine was titrated from 1.25 mg once daily at baseline to, at most, 10 mg three times daily by day 24 (mean final dose 22.4 mg/day). After 8 weeks, the tolcapone group had a significant reduction in daily levodopa dose compared with the bromocriptine group (p<0.05). No significant differences in the "on/off" time and motor disability were seen between the tolcapone and bromocriptine treatment groups. Bromocriptine induced more hallucinations, orthostatic hypotension, and nausea, whereas tolcapone therapy was associated with more muscle cramps and dystonia. These results suggest that when added to levodopa therapy, the two drugs have a different side effect profile, with the advantages for tolcapone being absence of titration and quicker efficacy.

Aged↗

PubMed1997

Tolcapone improves motor function and reduces levodopa requirement in patients with Parkinson's disease experiencing motor fluctuations: a multicenter, double-blind, randomized, placebo-controlled trial. Tolcapone Fluctuator Study Group I.

Tolcapone is a potent catechol-O-methyltransferase inhibitor that prolongs the plasma half-life of levodopa. This multicenter, double-blind, placebo-controlled study used two 10-hour clinical evaluations to compare the efficacy and safety of three doses of tolcapone (50, 200, and 400 mg tid) with placebo in patients with Parkinson's disease (PD) experiencing motor fluctuations from levodopa/carbidopa. One hundred fifty-one patients completed the study. Clinical evaluations lasting 10 hours were performed on day -1 and day 42 using United Parkinson's Disease Rating Scale motor subscale and "on/off" and dyskinesia assessments every 30 minutes. Tolcapone significantly reduced "off" time an average of 40% and increased total "on" time by about 25% at all dose levels, as compared to placebo treatment. Levodopa/carbidopa dosage and frequency were significantly reduced. Tolcapone was well tolerated, with patients experiencing typical dopaminergic side effects that could be reduced or eliminated by lowering levodopa/carbidopa dosages. Tolcapone was effective at prolonging the clinical benefit of levodopa and reducing total levodopa requirements in PD patients with motor fluctuations.

Aged↗

PubMed1997

Tolcapone, bromocriptine, and Parkinson's disease. French Tolcapone Study Group.

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Antiparkinson Agents↗

PubMed2001

Randomized trial of tolcapone versus pergolide as add-on to levodopa therapy in Parkinson's disease patients with motor fluctuations.

In this 12-week, randomized, open-label, blinded-rater, parallel-group trial, the efficacy, safety, and tolerability of tolcapone and pergolide were compared in parkinsonian patients with a fluctuating response to levodopa. Patients received tolcapone 100 mg three times daily (t.i.d.), with a possible increase to 200 mg t.i.d., or pergolide titrated to a maximum dose of 5 mg/day by week 9 (mean final dose 2.2 mg/day). The trial involved 203 patients. Efficacy variables that decreased from baseline to week 12 with tolcapone and pergolide included "off" time (reduced by 2-3 hours/day), daily levodopa intake, sickness impact profile scores, Parkinson's disease questionnaire (PDQ)-39 scores, and Unified Parkinson's Disease Rating Scale (UPDRS) scores. Improvements in efficacy variables were similar with tolcapone and pergolide, with the exception of improvements in quality of life, which were significantly greater with tolcapone; the relative changes in PDQ-39 score at week 12 were -8.7 and -14.2 (P < 0.05) with pergolide and tolcapone, respectively. Improvements in the investigator's global assessment (IGA) of overall efficacy were recorded in 86% of tolcapone-treated patients and in 78% of pergolide-treated patients. The proportion of patients who withdrew because of adverse events was higher in the pergolide group (15%) than in the tolcapone group (5%). Confusion, hypotension, nausea, constipation, abdominal pain, and dyspepsia occurred more frequently with pergolide, whereas diarrhea and urine discoloration occurred more frequently with tolcapone. Tolcapone was better tolerated than pergolide (P < 0.01) according to the IGA of overall tolerability. We conclude that, in this 3-month study, both tolcapone and pergolide provided improvements in motor fluctuations and allowed reductions in levodopa intake when added to levodopa therapy; intent to treat analysis and a less than maximal dose of pergolide may have biased the results in favor of tolcapone. Tolcapone provided greater improvements in quality of fife, was better tolerated, and had a more favorable adverse-event profile than pergolide.

Antiparkinson Agents↗

PubMedDate not supplied

Pharmacokinetics and pharmacodynamics of L-Dopa after acute and 6-week tolcapone administration in patients with Parkinson's disease.

Tolcapone, a central and peripheral catechol O-methyltransferase (COMT) inhibitor, reduces the conversion of L-Dopa into 3-O-methyl-Dopa (3-OMD), thus leading to more stable and sustained L-Dopa plasma levels. This study was designed to evaluate the effects of acute and 6-week tolcapone administration on L-Dopa pharmacokinetics and pharmacodynamics in Parkinson's disease (PD) patients with predictable motor fluctuations. Tapping test, walking time, and tremor, as well as L-Dopa and 3-OMD plasma levels, were assessed before and for 5 hours after the administration of a single L-Dopa dose, alone or in combination with 200 mg tolcapone, in seven patients with PD. This clinical and pharmacokinetic study was repeated after 6 weeks of tolcapone therapy (200 mg three times daily). It was observed that tolcapone, after both acute and chronic administration, prolonged the motor improvement induced by L-Dopa. As a result, at week 6 of tolcapone therapy, the daily hours spent "off" were significantly decreased. Tolcapone significantly increased the area under the curve of L-Dopa plasma levels by slowing down the elimination of L-Dopa from plasma, whereas the maximal concentration of L-Dopa was not modified. 3-OMD levels decreased significantly after acute tolcapone administration, and after 6 weeks of tolcapone therapy, they were approximately one sixth of pre-tolcapone values. The data confirm that tolcapone decreases L-Dopa clearance and prolongs motor response in PD patients with motor fluctuations, and that this effect is maintained after 6 weeks of tolcapone therapy.

Antiparkinson Agents↗

PubMed2006

Tolcapone: new drug. In Parkinson's disease: unacceptable risk of severe hepatitis.

(1) When patients with Parkinson's disease who are taking levodopa develop motor fluctuations that do not respond to dose adjustments, the standard treatment is the addition of bromocriptine, a dopaminergic agonist. Evaluation of entacapone fails to show whether the risk-benefit balance of this catechol-O-methyltransferase (COMT) inhibitor is at least as favourable as that of bromocriptine. (2) Tolcapone, another COMT inhibitor, is back on the French market after being withdrawn because of serious hepatic effects. The summary of product characteristics (SPC) specifies that tolcapone must only be used when entacapone treatment fails or is poorly tolerated. (3) Renewal of marketing authorisation was based on one clinical trial in which about half the patients were probably not resistant to entacapone. No difference in efficacy was found between tolcapone and entacapone. There is no firm evidence that tolcapone is effective in a significant number of patients in whom entacapone fails. (4) Placebo-controlled trials show that first-line treatment with tolcapone 100 mg to 200 mg 3 times a day reduces the duration of motor freezing ("off") periods, but the global impact of tolcapone on parkinsonism appears to be limited. (5) Unblinded randomised controlled trials have failed to show that tolcapone is more effective than bromocriptine or pergolide. There are no trials assessing the use of tolcapone in combination with dopamine agonists. (6) Adverse effects were frequent during clinical trials. They were mainly neurological and gastrointestinal, and differed from those associated with bromocriptine. In 1988, shortly after worldwide marketing of tolcapone, 3 cases of fatal fulminant hepatitis were reported among about 60 000 patients who had taken this drug. Some countries, including European Union member states, withdrew marketing authorisation. Other countries, including the United States, left tolcapone on the market but required stringent monitoring of liver function. Due to a lack of transparency on the part of both the manufacturer and the health authorities, we do not know if these measures reduced the risk of severe hepatitis. In the trial versus entacapone, one of the 75 patients treated with tolcapone 300 mg/day had an abnormal increase in serum transaminase activity. (7) In practice, tolcapone has a negative risk-benefit balance.

Antiparkinson Agents↗

PubMed1999

Effects of tolcapone upon soluble and membrane-bound brain and liver catechol-O-methyltransferase.

The present study was aimed to evaluate the sensitivity of soluble (S) and membrane bound (MB) catechol-O-methyltransferase (COMT) from rat brain and liver to inhibitors which interact with the enzyme as competitive (tropolone), non-competitive (S-adenosyl-l-homocysteine; SAHC) and tight-binding (tolcapone and 3,5-dinitrocatechol) inhibitors. COMT activity was evaluated by the ability to methylate adrenaline (0.1 to 2000 microM) to metanephrine in the presence of a saturating concentration of the methyl donor (S-adenosyl-l-methionine). When using a fixed amount of total protein (2 micrograms/ml), but variable concentrations of COMT, the inhibitory potency of tolcapone upon S- and MB-COMT activity in the brain was in the low nM range (IC50's of 2 and 3 nM, respectively), whereas in liver the IC50 values for tolcapone against liver MB- and S-COMT (IC50's of 123 and 795 nM, respectively) were markedly higher than those observed in the brain. By contrast, when inhibition studies were performed with a fixed concentration of COMT (15 nM), as determined by the Ackermann-Potter equation, tolcapone was found to be endowed with the same potency (in the low nM range) in inhibiting S- and MB-COMT from both brain and liver. As for tolcapone, 3,5-dinitrocatechol was more potent against MB- than against S-COMT when a fixed amount of total protein was used, but showed the same potency when a fixed concentration of COMT was used. Tropolone, a competitive inhibitor, was much less potent than tolcapone and 3,5-dinitrocatechol in inhibiting S- and MB-COMT from both brain and liver and its potency was found not to depend on enzyme concentration. SAHC, a non-competitive inhibitor, behaved similarly to tight-binding inhibitors when a fixed amount of total protein was used. By contrast, when a fixed amount of enzyme was used, SAHC was found to be endowed with the same potency against S- and MB-COMT from brain and liver. In the final series of experiments the inhibitory effect of tolcapone was examined under in vitro ex vivo conditions, using the same concentration of COMT (15 nM). One hour after its oral administration, tolcapone (0.3 to 30 mg/kg) was found to be much more potent against MB-COMT than against S-COMT. In the liver, 0.3 mg/kg tolcapone resulted in 82% inhibition of MB-COMT and 31% inhibition of S-COMT. In the brain, 3.0 mg/kg tolcapone inhibited 78% MB-COMT, whereas S-COMT activity was reduced by 38% only. In conclusion, the results reported here show that tolcapone is particularly potent in inhibiting MB-COMT from liver and brain under in vivo experimental conditions, though it does not discriminate between MB- and S-COMT under in vitro experimental conditions when using the same amount of enzyme in the assay.

Animals↗

PubMed1998

The effect of tolcapone on levodopa pharmacokinetics is independent of levodopa/carbidopa formulation.

Clinical pharmacology studies have shown that the catechol-O-methyltransferase inhibitor tolcapone increases the bioavailability area under the plasma concentration-time curve (AUC) and the plasma elimination half-life (t1/2) of levodopa. The objective of the study was to evaluate the pharmacokinetics of levodopa and 3-O-methyldopa (3-OMD) after coadministration of tolcapone 200 mg with levodopa/ carbidopa in the following doses: 100/10 mg, 100/25 mg, 200/20 mg, 200/50 mg, 250/25 mg (all immediate-release) and 200/50 mg (controlled-release). Thirty healthy male volunteers were divided into four groups: three groups of 8 and one group of 6. Participants in the first three groups received two formulations of levodopa/carbidopa. Each dose was administered on two occasions, once with tolcapone 200 mg and once with placebo (four-way crossover). In the fourth group, one formulation was given on two occasions, once with tolcapone 200 mg and once with placebo (two-way crossover). Dosing days were separated by a 7-day washout. The effect of tolcapone on levodopa and 3-OMD pharmacokinetics was found to be similar with all levodopa/carbidopa formulations. The absorption of levodopa was unaffected by tolcapone in all treatment groups and the maximum plasma concentration (Cmax) remained unchanged. When tolcapone was given with the immediate-release formulations, levodopa AUC increased by 60-90% and levodopa t1/2 by 20-60%. With tolcapone and the controlled-release formulation, AUC increased by 80% and t1/2 by 60%. With all levodopa/carbidopa formulations, 3-OMD Cmax decreased by 80% and AUC by 70% with tolcapone. The tolerability of all treatment combinations was similar. We conclude that adjunctive treatment with tolcapone should have similar levodopa-potentiating clinical effects, regardless of the levodopa/carbidopa formulation.

Administration, Oral↗

PubMed2005

The role of physicochemical properties of entacapone and tolcapone on their efficacy during local intrastriatal administration.

Aqueous solubility, apparent partition coefficient (logPapp) and catechol-O-methyltransferase (COMT, EC 2.1.1.6) inhibiting potency of entacapone and tolcapone were compared in vitro. Both drugs (at 10 and 100 microM) were also delivered directly into rat striatum via a microdialysis probe. Extracellular 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) concentrations were measured to evaluate the inhibition of striatal COMT in vivo. Although entacapone had 15-fold better aqueous solubility than tolcapone at pH 7.4, also tolcapone had sufficient aqueous solubility to remain in solution at 100 microM. The logPapp of tolcapone was higher than that reported for entacapone in the pH range from 5.0 to 7.4. Entacapone and tolcapone inhibited equally rat striatal COMT in vitro with Ki values of 1.86 and 2.50 nM, respectively. Both drugs had similar outflow from the microdialysis probe in vitro. Perfusion of 100 microM entacapone increased significantly extracellular DOPAC levels compared to the control group. Both entacapone and tolcapone (at 10 and 100 microM) decreased significantly HVA levels, but entacapone was significantly more effective than tolcapone at 100 microM. In conclusion, entacapone and tolcapone are equally potent COMT inhibitors against rat striatal COMT in vitro. After local intrastriatal administration, entacapone appeared to inhibit COMT faster and more effectively than the more lipophilic tolcapone. Thus, intrastriatal administration led to opposite results compared to those reported in the brain after systemic administration. The present results also suggest that the local distribution of entacapone and tolcapone differ when the drugs are delivered directly into the brain.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1997

Optimizing levodopa pharmacokinetics with multiple tolcapone doses in the elderly.

OBJECTIVES: The multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of tolcapone, a novel catechol-O-methyltransferase (COMT) inhibitor, were assessed in healthy elderly volunteers receiving concomitant carbidopa and levodopa. METHODS: Thirty-six volunteers from 55 to 75 years old participated in this double-blind, placebo-controlled, ascending multiple-dose study. Tolcapone was studied at dosages of 100, 200, 400, or 800 mg three times daily (t.i.d.) in four sequential groups. Each group consisted of nine participants who had been randomized to receive either placebo (n = 3) or tolcapone (n = 6). Tolcapone or placebo was coadministered with carbidopa and levodopa (25 and 100 mg, respectively) for 7 days. Assessments included tolerability, pharmacokinetics of tolcapone, levodopa, and 3-O-methyldopa, and inhibition of COMT activity in erythrocytes. RESULTS: By inhibiting COMT, tolcapone reduced levodopa metabolism to 3-O-methyldopa, resulting in a twofold increase in levodopa exposure (area under the curve) and elimination half-life, without changing levodopa peak plasma concentration. These effects were similar on days 1 and 7 of treatment. Development of tolerance to COMT inhibition was not observed. Onset of effect was rapid (day 1 of treatment), and the maximum effect on levodopa pharmacokinetics was already observed with 100 or 200 mg tolcapone t.i.d. At these dosages, tolcapone pharmacokinetics were linear and stable; accumulation occurred with 800 mg t.i.d. The combination of tolcapone and carbidopa-levodopa was generally well tolerated, although more nausea and vomiting were observed at higher dosages (400 to 800 mg t.i.d.), particularly in women. CONCLUSION: Tolcapone shows promise as an effective adjunct to levodopa in the treatment of Parkinson's disease. Clinical pharmacology data indicate that the therapeutic regimen should be 100 or 200 mg t.i.d.

Administration, Oral↗

PubMed2003

Pharmacokinetics and pharmacodynamics of entacapone and tolcapone after acute and repeated administration: a comparative study in the rat.

Two catechol-O-methyltransferase (COMT) inhibitors, entacapone and tolcapone, were compared in the rat to elucidate the actual differences between their pharmacokinetics and pharmacodynamics after single and repeated administration. Their inhibitory potencies were also compared in vitro. After intravenous administration (3 mg/kg), the elimination half-life (t(1/2 beta)) of entacapone (0.8 h) was clearly shorter than that of tolcapone (2.9 h). The striatum/serum ratio of tolcapone was 3-fold higher than that of entacapone. After a single oral dose (10 mg/kg), both entacapone and tolcapone produced an equal maximal degree of COMT inhibition in peripheral tissues, but tolcapone inhibited striatal COMT more effectively than did entacapone. After the 7-day treatment (10 mg/kg twice daily), COMT activity had recovered to a level of 67 to 101% of control within 8 h after the last dose of entacapone. In tolcapone-treated animals, there was still extensive COMT inhibition present in peripheral tissues, and the degree of inhibition was higher than that attained after a single dose. The pharmacokinetic-pharmacodynamic modeling revealed that a plateau of COMT inhibition near the maximal attainable inhibition was reached already by plasma concentrations below 2000 ng/ml, both with entacapone and tolcapone. Entacapone and tolcapone inhibited equally rat liver COMT in vitro with K(i) values of 10.7 and 10.0 nM, respectively. In conclusion, tolcapone has a longer duration of action and a better brain penetration than entacapone. The results also suggest that peripheral COMT is inhibited continuously when tolcapone is dosed at 12-h intervals, but this was not seen with entacapone.

Administration, Oral↗

PubMed2006

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 > or = 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 > or = 3 times the ULN were infrequent.

Adult↗