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PubMed1999

Tolcapone (Tasmar)

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Antiparkinson Agents↗
PubMed1999

Tolcapone withdrawn.

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PubMed2000

Clinical pharmacology, therapeutic use and potential of COMT inhibitors in Parkinson's disease.

When peripheral decarboxylation is blocked by carbidopa or benserazide, the main metabolic pathway of levodopa is O-methylation by catechol-O-methyltransferase (COMT). Entacapone and tolcapone are new potent, selective and reversible nitrocatechol-type COMT inhibitors. Animal studies have demonstrated that entacapone mainly has a peripheral effect whereas tolcapone also inhibits O-methylation in the brain. In human volunteers, both entacapone and tolcapone dose-dependently inhibit the COMT activity in erythrocytes, improve the bioavailability and decrease the elimination of levodopa, and inhibit the formation of 3-O-methyldopa (3-OMD). Entacapone is administered with every scheduled dose of levodopa whereas tolcapone is administered 3 times daily. The different administration regimens for these agents are based on their different pharmacokinetic and pharmacodynamic profiles. Both entacapone and tolcapone enhance and extend the therapeutic effect of levodopa in patients with advanced and fluctuating Parkinson's disease. They prolong the duration of levodopa effect. Clinical studies show that they increase the daily ON time by an average 1 to 3 hours, improve the activities of daily living and allow daily levodopa dosage to be decreased. Correspondingly, they significantly reduce the daily OFF time. No comparative studies between entacapone and tolcapone have been performed. Tolcapone also appears to have a beneficial effect in patients with nonfluctuating Parkinson's disease. The main adverse effects of the COMT inhibitors are related to their dopaminergic and gastrointestinal effects. Enhancement of dopaminergic activity may cause an initial worsening of levodopa-induced adverse effects, such as dyskinesia, nausea, vomiting, orthostatic hypotension, sleep disorders and hallucinations. Levodopa dose adjustment is recommended to avoid these events. Tolcapone is associated with diarrhoea in about 16 to 18% of patients and entacapone in less than 10% of patients. Diarrhoea has led to discontinuation in 5 to 6% of patients treated with tolcapone and in 2.5% of those treated with entacapone. Urine discoloration to dark yellow or orange is related to the colour of COMT inhibitors and their metabolites. Elevated liver transaminase levels are reported in 1 to 3% of patients treated with tolcapone but very rarely, if at all, in patients treated with entacapone. The descriptions of acute, fatal fulminant hepatitis and potentially fatal neurological reactions, such as neuroleptic malignant syndrome and rhabdomyolysis, in association with tolcapone led to the suspension of its marketing authorisation in the European Community and Canada. In many other countries, the use of tolcapone is restricted to patients who are not responding satisfactorily to other therapies. Regular monitoring of liver enzymes is required if tolcapone is used. No such adverse reactions have so far been described for entacapone and no laboratory monitoring has been proposed. COMT inhibitors added to levodopa therapy are beneficial, particularly in patients with fluctuating disease. They may be combined with other antiparkinsonian drugs, such as dopamine agonists, selegiline and anticholinergics without adverse interactions. They provide a new treatment possibility in patients with Parkinson's disease who have problems with their present levodopa therapy.

Antiparkinson Agents↗
PubMed2002

Entacapone does not induce conformational changes in liver mitochondria or skeletal muscle in vivo.

Entacapone and tolcapone, novel catechol-O-methyl-transferase (COMT) inhibitors, have been developed for the treatment of Parkinson's disease in combination with levodopa. Three fatal cases of drug-induced hepatitis, one with hepatic necrosis and mitochondrial changes have been reported in clinical use of tolcapone. In vitro tolcapone has been shown to induce uncoupling of oxidative phosphorylation. Liver and skeletal muscle tissues from an oral rat toxicity study were used to investigate the influence of entacapone, tolcapone (300 and 500 mg/kg/day) or a known uncoupling agent, 2,4-dinitrophenol (DNP), (20 mg/kg/ day) on the cell morphology. Centrolobular hypertrophy was revealed in the histopathology of the liver in tolcapone-treated rats. Transmission electron microscopy (TEM) of the liver and skeletal muscle tissue, revealed mitochondrial swelling and reduced matrix density with deformation of cristae in the tolcapone and DNP groups. Intermyofibrillar edema was characteristic of the skeletal muscle tissue of DNP- and tolcapone-exposed animals. In the tolcapone group, also the sarcomeres were prominent. Treatment-related light microscopic or TEM findings were not observed either in entacapone-treated or control animals. The similarity of structural damages induced by both tolcapone- and DNP suggests that uncoupling of oxidative phosphorylation may contribute to the toxicity of tolcapone in the rat.

2,4-Dinitrophenol↗
PubMed2004

Catechol-O-methyltransferase inhibitors versus active comparators for levodopa-induced complications in Parkinson's disease.

BACKGROUND: As Parkinson's disease progresses the control of the symptoms often requires the addition of other drugs to levodopa. The principle aim of COMT inhibitor therapy is to increase the duration of effect of the levodopa dose and thus reduce the time patients spend in the relatively immobile 'off' phase. OBJECTIVES: To compare the efficacy and safety of adjuvant COMT inhibitor therapy versus active comparators in patients with Parkinson's disease, already established on levodopa and suffering from motor complications. SEARCH STRATEGY: Electronic searches of the Cochrane Controlled Trials Register (The Cochrane Library Issue 1, 2003), MEDLINE (1966-2003), EMBASE (1974-2003), were conducted. Grey literature was hand searched and the reference lists of identified studies and reviews examined. The manufacturers of COMT inhibitors were contacted. SELECTION CRITERIA: Randomised controlled trials of adjuvant COMT inhibitor therapy versus an active comparator in patients with a clinical diagnosis of idiopathic Parkinson's disease and long-term complications of levodopa therapy. DATA COLLECTION AND ANALYSIS: Data was abstracted independently by the authors and differences settled by discussion. The outcome measures used included Parkinson's disease rating scales, levodopa dosage, 'off' time measurements and the frequency of withdrawals and adverse events. MAIN RESULTS: Two trials were found that examined the efficacy of a COMT inhibitor against an active comparator (n = 349). Koller 1998 compared the efficacy of tolcapone versus pergolide (n = 203) over 12 weeks and TSG 1999 compared the efficacy of tolcapone versus bromocriptine (n = 146) over 8 weeks. No trials were found that compared entacapone with active comparators. Tolcapone produced similar benefits to bromocriptine in 'off' time reduction, motor impairment and disability ratings over three months of therapy. Tolcapone produced a greater reduction in levodopa dosage than bromocriptine. Tolcapone produced similar benefits to pergolide in levodopa dose reduction, motor impairment and disability ratings, and in generic health-related quality of life scales over the first two months of therapy. Tolcapone produced a greater improvement in the disease-specific quality of life scale PDQ-39 than pergolide. Nausea, constipation and orthostatic complaints were greater with agonist therapy, but otherwise the frequency of adverse events and withdrawals from treatment were similar with the two classes of adjuvant medication. One patient had significantly elevated liver enzymes whilst on tolcapone, but otherwise the frequency of adverse events and withdrawals from treatment were similar. REVIEWERS' CONCLUSIONS: The two trials comparing tolcapone with the dopamine agonists bromocriptine and pergolide were underpowered to detect clinically relevant differences between them. This is based on medium-term evidence. No evidence was found comparing entacapone with active comparators. Further larger and longer-term trials are required to compare tolcapone with entacapone and COMT inhibitor therapy with alternative adjuvant classes of drug in later Parkinson's disease such as dopamine agonists and monoamine oxidase inhibitors.

Antiparkinson Agents↗
PubMed2002

Different toxicological profile of two COMT inhibitors in vivo: the role of uncoupling effects.

The toxicity profiles of entacapone and tolcapone, novel catechol- O-methyl-transferase (COMT) inhibitors, have been reported to differ from each other. It has also been shown that tolcapone, but not entacapone, is a potent uncoupler of oxidative phosphorylation in vitroat low micromolar concentrations. Signs of hepatotoxicity induced by tolcapone treatment have been previously reported in toxicological studies and in clinical use. The present study was designed to investigate the mechanism of hepatotoxicity of tolcapone and its possible relationship to uncoupling of oxidative phosphorylation in vivo. A 15-day oral toxicity study with entacapone or tolcapone (300 and 500 mg/kg/day) was carried out, and 2, 4-dinitrophenol (DNP), a known uncoupling agent of oxidative phosphorylation, served as a positive reference substance (20 mg/kg/day). No treatment related findings were observed in entacapone-treated rats. Clinical chemistry parameters regarding hepatocellular damage were increased in tolcapone and DNP-treated animals. The energy status measured as ATP/ADP ratio from the liver samples and energy charge (EC) in liver cell mitochondria were diminished both in tolcapone- and in DNP-treated rats. These signs together with clinical symptoms consisting of increased respiration, decreased activity and drowsiness, and elevation of the rectal body temperature observed in tolcapone- and DNP-treated animals suggest a relationship between the treatment and uncoupling of oxidative phosphorylation in vivo.

Animals↗
PubMed2003

Effects of peripheral and central catechol-O-methyltransferase inhibition on striatal extracellular levels of dopamine: a microdialysis study in freely moving rats.

Tolcapone is a mixed (peripheral and central) catechol-O-methyltransferase (COMT) inhibitor, whereas entacapone is a preferential peripheral COMT inhibitor. Both drugs are able to decrease the peripheral conversion of L-DOPA into 3-O-methyl-DOPA and thereby increase plasma and cerebral levels of L-DOPA, the precursor of dopamine (DA). Tolcapone may also impair the extraneuronal catabolism of DA by inhibiting COMT activity in the brain. To evaluate the role played by peripheral and central COMT inhibition, we compared the effects of tolcapone and entacapone on COMT activity in peripheral tissues, and on striatal extracellular levels of L-DOPA and DA in rats. Tolcapone and entacapone, at the dose of 15 mg/kg p.o., were almost equally effective in inhibiting COMT activity in duodenum and liver. Tolcapone decreased striatal extracellular levels of homovanillic acid (HVA), thus confirming its central COMT inhibitory effect, whereas entacapone did not alter HVA efflux. Following L-DOPA/benserazide administration (50/15 mg/kg p.o.), both COMT inhibitors significantly increased striatal levels of L-DOPA and DA compared with saline. The levels of L-DOPA were similar after treatment with either COMT inhibitors, whereas the increase in DA output was significantly greater in rats given tolcapone compared to those given entacapone. We conclude that the blockade of central DA catabolism by tolcapone contributes to the greater increase in striatal DA levels achieved with this drug.

Animals↗
PubMed2004

Catechol-O-methyltransferase inhibitors for levodopa-induced complications in Parkinson's disease.

BACKGROUND: As Parkinson's disease progresses the control of motor symptoms often requires the addition of other drugs to levodopa. The principle aim of COMT inhibitor therapy is to increase the duration of effect of each levodopa dose and thus reduce the time patients spend in the relatively immobile 'off' phase. OBJECTIVES: To compare the efficacy and safety of adjuvant COMT inhibitor therapy versus placebo in patients with Parkinson's disease, already established on levodopa and suffering from motor complications. SEARCH STRATEGY: Electronic searches of the Cochrane Controlled Trials Register, (The Cochrane Library Issue 1, 2003), MEDLINE (1966-2003), EMBASE (1974-2003), were conducted. Grey literature was hand searched and the reference lists of identified studies and reviews examined. The manufacturers of COMT inhibitors were contacted. SELECTION CRITERIA: Randomised controlled trials of adjuvant COMT inhibitor therapy versus a placebo in patients with a clinical diagnosis of idiopathic Parkinson's disease and long-term complications of levodopa therapy. DATA COLLECTION AND ANALYSIS: Data were abstracted independently by the authors and differences settled by discussion. The outcome measures used included Parkinson's disease rating scales, levodopa dosage, 'off' time measurements and the frequency of withdrawals and adverse events. MAIN RESULTS: Fourteen trials fulfilled the inclusion criteria. 2566 patients with Parkinson's disease and motor fluctuations were included in this review. Eight trials examined entacapone versus placebo in a total of 1560 patients. These trials were between two and twelve months in duration. Six trials examined tolcapone versus placebo in a total of 1006 patients. These trials were between six weeks and twelve months in duration. Both tolcapone and entacapone reduced 'off' time, reduced levodopa dose and modestly improved motor impairments and disability. This was at the expense of increased risk of dyskinesias, nausea, vomiting, and diarrhoea. A few participants taking tolcapone were found to have raised liver enzyme levels. REVIEWERS' CONCLUSIONS: In the management of the motor complications seen in Parkinson's disease, tolcapone and entacapone can be used to reduce off time, reduce levodopa dose, and modestly improve motor impairment and disability. This is based on, at best, medium term evidence. However some participants on tolcapone had raised liver enzymes. This combined with three cases of fatal hepatic toxicity found during post-marketing surveillance has raised concerns over the safety of tolcapone.

Antiparkinson Agents↗