nitrophenols and Parkinson-Disease

Entacapone and tolcapone are reversible COMT inhibitors which have been approved for clinical use in patients with Parkinson disease (PD). Nebicapone is a third COMT inhibitor which has been studied in humans. COMT inhibitors are used in combination with levodopa and a dopa decarboxylase (DDC) inhibitor. Each of them has problems either in pharmacokinetics, pharmacodynamics, clinical efficacy, or in safety. All three inhibitors have short elimination half-lives, about 2-3h. Tolcapone is longer acting and more potent COMT inhibitor than entacapone; nebicapone lies in between. However, none of the present inhibitors cause a complete peripheral COMT inhibition. Tolcapone and nebicapone have increased more levodopa AUC than entacapone which is reflected also in their clinical efficacy. The most common adverse event with COMT inhibitors is dyskinesia which is usually managed by decreasing levodopa dose. The greatest problem with tolcapone and probably also with nebicapone is their liver toxicity which is not seen with entacapone. Tolcapone causes severe diarrhea more often than entacapone. Though the present COMT inhibitors have improved significantly the treatment of advanced PD patients, they still have several problems and weaknesses leaving room for developing better COMT inhibitors.

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Humans; Levodopa; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

The first effective drugs for Parkinson's disease (PD) were anticholinergics, introduced at the end of 19.th century by Charcot. Since the introduction of levodopa in the sixties of the previous century, many new drugs have emerged for the treatment of Parkinson's disease: dopamine agonists (ergot as well as non-ergot, bromocriptine, pergolide, mirapexine, ropinirole), MAO B inhibitors (selegiline, rasagiline), amantadine, COMT inhibitors (entacapone, tolcapone). In all stages of the disease, levodopa remains the most effective drug for improving motor symptoms in PD. However, long term treatment with levodopa is accompanied by the development of motor fluctuations, dyskinesia, cognitive and neuropsychiatric adverse effects and increasingly diverse spectrum of drugs is needed to alleviate motor and nonmotor symptoms. Some of these drugs have caused considerable concern and controversies and were regarded at certain points as the 'bad guys' of Parkinson's disease pharmacological armamentarium. In the article, a short review of 'bad guys' including anticholinergics, selegiline, tolcapone and dopamine agonists, is given.

Topics: Antiparkinson Agents; Benzophenones; Cholinergic Antagonists; Cognition; Dopamine Agonists; Humans; Levodopa; Nitrophenols; Parkinson Disease; Randomized Controlled Trials as Topic; Selegiline; Survival Rate; Tolcapone; Treatment Outcome

Levodopa has been the gold standard therapy for the motor symptoms of Parkinson's disease for more than three decades. Although it remains the most effective treatment, its long-term use is associated with motor fluctuations and dyskinesias that can be disabling for patients and difficult for physicians to manage medically. In the last 10 years, the catechol-O-methyltransferase (COMT) inhibitor tolcapone has been studied for its efficacy as an adjunctive treatment to levodopa plus a dopa decarboxylase inhibitor. Adjunctive therapy with tolcapone can significantly reduce the dose of levodopa required. Moreover, treatment with tolcapone significantly reduces wearing off and on-off periods in fluctuating patients and improves 'on' time in patients with stable disease. Tolcapone has assumed a new place in the arsenal of medications for Parkinson's disease. This paper reviews the pharmacology, safety and efficacy of tolcapone in patients with advanced Parkinson's disease. After some initial concerns about its safety, tolcapone has been shown to be safe if used and monitored according to guidelines regarding liver function. Tolcapone produces expected dopaminergic side effects, including headache, nausea, insomnia, as well as diarrhea; however, these side effects are generally mild and as a rule do not result in discontinuation of therapy.

Topics: Antiparkinson Agents; Benzophenones; Drug-Related Side Effects and Adverse Reactions; Humans; Levodopa; Nitrophenols; Parkinson Disease; Tolcapone; Treatment Outcome

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.

Topics: Aged; Antiparkinson Agents; Benzophenones; Catechols; Dose-Response Relationship, Drug; Evidence-Based Medicine; Female; Humans; Male; Meta-Analysis as Topic; Middle Aged; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Humans; Nitrophenols; Parkinson Disease; Tolcapone

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.

Topics: Antiparkinson Agents; Benzophenones; Clinical Trials as Topic; Humans; Nitrophenols; Parkinson Disease; Tolcapone

Although levodopa remains the gold standard treatment for Parkinson's disease, many patients develop motor complications with chronic levodopa exposure. Tolcapone is a catechol-O-methyltransferase inhibitor that extends the action of levodopa. When used in conjunction with levodopa, tolcapone has been shown to be effective in improving motor fluctuations and reducing levodopa requirements in Parkinson's disease patients. However, rare reports of severe hepatotoxicity have limited its use. A recent review of the data on tolcapone-treated patients suggests that, with proper monitoring of liver function, the potential for hepatotoxicity with tolcapone use is negligibly small.

Topics: Animals; Benzophenones; Drug Synergism; Drug Therapy, Combination; Humans; Levodopa; Nitrophenols; Parkinson Disease; Tolcapone

Diagnosis of PD can be difficult in elderly patients because some of the key PD symptoms also may be manifestations of normal aging. Asymmetrical symptom onset, resting tremor,and sustained response to levodopa are key features that suggest a diagnosis of PD. For most patients, PD progresses fairly slowly. The goal of treatment is to control symptoms, thereby allowing quality of life and functional ability to be maintained. Pharmacologic therapies are primarily targeted at stimulating dopaminergic receptors, either by increasing the levels of dopamine or by using dopamine agonists. Levodopa, the main therapy for PD and a precursor of dopamine, has a short half-life and is quickly metabolized.Accordingly, decarboxylase inhibitors, like carbidopa, are almost always administered with levodopa to prevent breakdown in the periphery. Catechol-O-methyltransferase (COMT)inhibitors, which increase dopamine levels by inhibiting the metabolism of levodopa and dopamine, recently have become available, including a tablet containing carbidopa, levodopa,and entacapone. Other pharmaceutical therapies for PD include dopamine agonists, monoamine oxidase-B (MAO-B) inhibitors, anticholinergic agents, and amantadine. Dopamine agonists, anticholinergic agents, and amantadine are associated with an increased risk of hallucinations or other adverse events in elderly patients; therefore, use of these should be avoided in this population. Surgical management, particularly deep brain stimulation(DBS), is an option for patients who are refractory to pharmaceutical therapy. Although patients may not need levodopa as an initial treatment, over time most patients will require this drug to control symptoms. With chronic levodopa therapy, patients ultimately experience a wearing off in levodopa response and other motor complications. Management of wearing off is a significant challenge in the treatment of patients with advanced PD.

Topics: Aged, 80 and over; Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Dopamine Agonists; Female; Humans; Levodopa; Male; Monoamine Oxidase Inhibitors; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

Fluctuating Parkinson's disease (PD) represents a clinical management challenge. The primary utility of levodopa in patients with PD is moderated by the "wearing off" phenomena seen with long-term use. COMT inhibitors slow down the rapid metabolism of levodopa, resulting in a more-sustained response to dopaminergic therapy. Tolcapone is a selective, reversible catechol-O-methyltransferase (COMT) inhibitor, shown to have both peripheral and central effects. In clinical trials, tolcapone has been shown to reduce "off" time, increase "on" time, improve patient and clinician assessments of disease severity, and improve patient quality of life. In a SWITCH study, tolcapone was associated with greater duration of "on" time than remaining on entacapone. Adverse effects of tolcapone are related to the class, with the exception of rare cases of hepatotoxicity. Tolcapone has been recently reintroduced on the European market and recent guidance from the US Food and Drug Administration has reduced the hepatic monitoring requirements for patients initiating tolcapone therapy. With proper monitoring, tolcapone is an effective, well-tolerated drug useful in the management of patients with fluctuating PD.

Topics: Antiparkinson Agents; Benzophenones; Drug Synergism; Female; Humans; Levodopa; Male; Middle Aged; Nitrophenols; Parkinson Disease; Periodicity; Severity of Illness Index; Tolcapone

Tolcapone (Tasmar) is a selective, reversible inhibitor of peripheral and central catechol-O-methyltransferase (COMT). Results of well designed studies indicate that oral tolcapone is an effective adjunct to levodopa plus a peripheral dopa-decarboxylase inhibitor (DDCI) in patients with fluctuating Parkinson's disease. Tolcapone significantly improves levodopa-induced motor fluctuations and significantly reduces levodopa requirements. The drug is generally well tolerated, with the most commonly occurring adverse events being dopaminergic related. Thus, tolcapone is a useful option in patients with fluctuating Parkinson's disease who are receiving levodopa/DDCI and are not responding to, or are not candidates for, other adjunctive treatments.

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Routes; Drug Evaluation; Drug Therapy, Combination; Humans; Nitrophenols; Parkinson Disease; Tolcapone; Treatment Outcome

Parkinson's disease patients treated with a combination of levodopa and an aromatic L-amino acid decarboxylase inhibitor usually develop motor complications after some years. To minimise this problem, selective catechol-O-methyltransferase (COMT) inhibitors were developed in order to improve the poor pharmacokinetic profile of levodopa. Tolcapone and entacapone are the two marketed drugs in this class, and both increase the half-life of levodopa and improve clinical parameters, such as the increase in the duration of 'on' and decrease of 'off' time. Soon after its release, tolcapone was suspended in the EU due to it's implication in the deaths of three Parkinsonian patients. The cause of death in these patients was fulminant hepatitis. The mechanism by which tolcapone induces liver damage has been studied. Results show that this drug induces uncoupling of oxidative phosphorylation in mitochondria, thus significantly reducing the cell's capacity to generate ATP. This toxic effect was demonstrated both in vitro and in vivo in several models but the concentrations required to induce it are significantly higher than those needed to inhibit COMT. Inter-individual differences in the capacity to metabolise tolcapone may yield higher plasma levels and may explain its toxic effects in a small sample of patients. Recently, the suspension on tolcapone was lifted, based on new clinical data and ongoing monitoring of its use in other countries. The European Agency for the Evaluation of Medicinal Products concluded that, in some situations, tolcapone has a clinical efficacy that is superior to entacapone and that an adequate level of safety could be achieved with appropriate liver function monitoring and other measures. It is concluded that tolcapone can be safely used in Parkinsonian patients who do not respond or cannot, for other reasons, be prescribed with other COMT inhibitors.

Topics: Adenosine Triphosphate; Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Chemical and Drug Induced Liver Injury; Half-Life; Humans; Levodopa; Liver; Mitochondria; Nitrophenols; Oxidative Stress; Parkinson Disease; Phosphorylation; Safety; Tolcapone

The objective of this study is to update a previous evidence-based medicine (EBM) review on Parkinson's disease (PD) treatments, adding January 2001 to January 2004 information. The Movement Disorder Society (MDS) Task Force prepared an EBM review of PD treatments covering data up to January 2001. The authors reviewed Level I (randomized clinical trials) reports of pharmacological and surgical interventions for PD, published as full articles in English (January 2001-January 2004). Inclusion criteria and ranking followed the original program and adhered to EBM methodology. For Efficacy Conclusions, treatments were designated Efficacious, Likely Efficacious, Non-Efficacious, or Insufficient Data. Four clinical indications were considered for each intervention: prevention of disease progression; treatment of Parkinsonism, as monotherapy and as adjuncts to levodopa where indicated; prevention of motor complications; treatment of motor complications. Twenty-seven new studies qualified for efficacy review, and others covered new safety issues. Apomorphine, piribedil, unilateral pallidotomy, and subthalamic nucleus stimulation moved upward in efficacy ratings. Rasagiline, was newly rated as Efficacious monotherapy for control of Parkinsonism. New Level I data moved human fetal nigral transplants, as performed to date, from Insufficient Data to Non- efficacious for the treatment of Parkinsonism, motor fluctuations, and dyskinesias. Selegiline was reassigned as Non-efficacious for the prevention of dyskinesias. Other designations did not change. In a field as active in clinical trials as PD, frequent updating of therapy-based reviews is essential. We consider a 3-year period a reasonable time frame for published updates and are working to establish a Web-based mechanism to update the report in an ongoing manner.

Topics: Amantadine; Antiparkinson Agents; Apomorphine; Benzophenones; Benzothiazoles; Bromocriptine; Cabergoline; Catechol O-Methyltransferase Inhibitors; Deep Brain Stimulation; Dihydroergocryptine; Ergolines; Fetal Tissue Transplantation; Globus Pallidus; Humans; Indans; Indoles; Levodopa; Lisuride; Mesencephalon; Monoamine Oxidase Inhibitors; Neurosurgical Procedures; Nitrophenols; Parkinson Disease; Pergolide; Piribedil; Pramipexole; Selegiline; Thiazoles; Tolcapone

Although levodopa remains the most effective drug for the symptomatic treatment of Parkinson's disease (PD), there are significant limitations to its chronic use. Growing preclinical and clinical evidence suggests that the severity of motor fluctuations is influenced both by PD severity and pulsatile stimulation of striatal dopamine receptors. Current management of motor fluctuations is based primarily on strategies to prolong the effects of dopaminergic stimulation. This prolongation is accomplished either through the use of long-acting dopaminergic drugs or prolonging of the effects of levodopa. During the past decade, the armamentarium of dopamine agonists increased and agents that prolong the plasma half-life of levodopa became available. Furthermore, recent clinical trials provide evidence-based approaches to improve the management of motor fluctuations in patients with advanced and early PD.

Topics: Apomorphine; Benzophenones; Cabergoline; Catechol O-Methyltransferase Inhibitors; Catechols; Dopamine Agonists; Ergolines; Humans; Levodopa; Movement Disorders; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

Combining levodopa with the catechol-O-methyltransferase (COMT) inhibitor entacapone has been shown to be an effective strategy in the management of Parkinson's disease (PD) patients experiencing motor fluctuations. Safety and tolerability information has come from postmarketing surveillance studies as well as several randomized, placebo-controlled trials with long-term open-label extension phases specifically investigating the safety and tolerability of levodopa plus entacapone. Results show the most common dopaminergic side effects to be dyskinesia and nausea, which result from the increased bioavailability of levodopa and can be readily managed. Non-dopaminergic side effects include diarrhea and harmless urine discoloration. There is no convincing evidence of hepatic injury with entacapone use, and therefore monitoring of liver enzymes is unnecessary. With over 300,000 patient-years of exposure, levodopa combined with entacapone can be considered safe and well tolerated.

Topics: Aged; Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Clinical Trials as Topic; Dyskinesia, Drug-Induced; Enzyme Inhibitors; Female; Humans; Liver; Male; Nausea; Nitriles; Nitrophenols; Parkinson Disease; Safety; Tolcapone

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.. 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.. 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.. 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 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.. 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.. 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.

Topics: Antiparkinson Agents; Benzophenones; Bromocriptine; Catechol O-Methyltransferase Inhibitors; Dopamine Agonists; Humans; Levodopa; Nitrophenols; Parkinson Disease; Pergolide; Tolcapone

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.. 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.. 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.. 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 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.. 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.. 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.

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Enzyme Inhibitors; Humans; Levodopa; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

An essential element of pharmaceutical development, defined as the period between the discovery of a new agent and its market release, is provided by the "preclinical studies". They consist of the in vitro and in vivo studies performed before examination of the agent in human subjects. Regulatory authorities prescribe specific requirements regarding the nature and number of preclinical studies. In the present paper, we discuss the relevance of these studies for the treatment of Parkinson's disease (PD) on the basis of three examples: the L-DOPA ( L-3,4-dihydroxyphenylalanine, levodopa) story; the development of selegiline as a palliative and neuroprotective drug; and the safety concerns regarding tolcapone, an inhibitor of central and peripheral catechol-O-methyltransferase (COMT).

Topics: Antiparkinson Agents; Benzophenones; Drug Evaluation, Preclinical; Humans; Levodopa; Neuroprotective Agents; Nitrophenols; Parkinson Disease; Selegiline; Tolcapone

Entacapone and tolcapone are selective catechol-O-methyltransferase (COMT) inhibitors developed recently as adjuncts to levodopa for the treatment of Parkinson's disease (PD). They extend the duration of action of levodopa. As a result, they increase 'on' time, decrease 'off' time and improve motor scores in patients with motor fluctuations. Both benefits and main side effects are related to increased dopaminergic activity. This paper reviews the use of those COMT inhibitors in PD with particular focus on the issue of hepatotoxicity. Neither tolcapone nor entacapone caused hepatotoxicity in preclinical studies. However, in 1998, four patients who were using tolcapone presented with serious liver dysfunction; three of them died due to acute liver failure. Tolcapone is now known to have the potential to cause hepatotoxicity in clinical use and experimental studies. It is now recommended that tolcapone be administered only in patients with motor fluctuations who are no longer satisfactorily treated with other medications for PD. Routine liver monitoring is now mandatory with this agent. Entacapone has been described as a well-tolerated and safe drug in recent experimental studies, human clinical trials and postmarketing surveillance. It can be offered to any patient with motor fluctuations and routine liver monitoring is not required.

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Chemical and Drug Induced Liver Injury; Chemical and Drug Induced Liver Injury, Chronic; Enzyme Inhibitors; Humans; Levodopa; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

Levodopa is the cornerstone of idiopathic Parkinson's disease (PD) treatment. However, after long-term use of levodopa, a significant percentage of patients experience motor fluctuations, which worsen their quality of life. Catechol-O-methyltransferase (COMT) inhibitors reduce levodopa metabolism and enhance the respective plasma levels, resulting in improvements in symptoms and overall quality of life. Tolcapone was the first drug of this class to be marketed, but was withdrawn in the European Union due to its implication in the deaths of three PD patients due to hepatic failure. Three deaths from fulminant hepatic failure in 40000 patient-years is a number that is 10-100 times higher than the expected incidence in the general population and, according to the manufacturer's own information, the number is probably underestimated due to under-reporting of cases. In the US, tolcapone was not withdrawn, but restrictive liver enzyme monitoring measures were issued by authorities, which severely limited its use. No further deaths from hepatic failure were reported since these measures were implemented. The mechanisms by which tolcapone may induce liver toxicity are still under debate. It was thought that mitochondrial uncoupling of oxidative phosphorylation by tolcapone, and consequent impairment of energy production by hepatocytes, could be responsible for the observed effects. Some experts consider that the restrictive guidelines issued in the US regarding tolcapone use may be loosened with no consequential reductions in safety. It was suggested that ongoing clinical information about safety should be considered and periodical revisions of the restrictions made accordingly. The identification of the molecular and biochemical basis of tolcapone hepatotoxicity, when completed, should also provide important indications for the clinical use of this drug. In conclusion, appropriate monitoring of liver function can ensure adequate safety in PD patients receiving tolcapone, who can therefore benefit from the symptomatic improvements obtained with this drug.

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Chemical and Drug Induced Liver Injury; Humans; Liver Function Tests; Nitrophenols; Parkinson Disease; Tolcapone

The symptoms of Parkinson's disease can become increasingly difficult to control as the disease advances, particularly with the development of motor complications, such as end-of-dose wearing-off and dyskinesias, following long-term therapy. At this stage, the patient is frequently referred to a Parkinson's disease specialist for advice on the management of their disease. In this review we provide an overview of the Parkinson's disease specialist's strategies for coping with such problems. This includes strategy to prevent or delay motor fluctuations and the concept of the long duration response. The paper also includes establishing the optimum and most rational levodopa treatment schedule, improving levodopa absorption, use of COMT-inhibition, the addition of oral dopaminergic agonists, and the use of subcutaneous injections or infusions of apomorphine or lisuride. Finally, we highlight the increasing importance of treatment strategies that stimulate dopamine receptors in a more continuous, less pulsatile manner as a way of reducing the risk of developing treatment-associated motor complications.

Topics: Antiparkinson Agents; Apomorphine; Benzophenones; Dyskinesias; Enzyme Inhibitors; Humans; Levodopa; Nitrophenols; Parkinson Disease; Tolcapone

Topics: Antiparkinson Agents; Benzophenones; Brain; Catechol O-Methyltransferase Inhibitors; Catechols; Humans; Nitriles; Nitrophenols; Parkinson Disease; Psychomotor Disorders; Randomized Controlled Trials as Topic; Tolcapone

Topics: Benzophenones; Bromocriptine; Cabergoline; Dopamine Agonists; Drug Therapy, Combination; Enzyme Inhibitors; Ergolines; Ergot Alkaloids; Humans; Levodopa; Lisuride; Nitrophenols; Parkinson Disease; Pergolide; Randomized Controlled Trials as Topic; Tolcapone

Antiparkinsonian agents applied or under the investigation for the treatment of patients with Parkinson's disease were reviewed. Tremor, akinesia, rigidity and postual instability are key signs of Parkinson's disease. The most important one is akinesia, which includes decreased spontaneous locomotor activity, slowness of movement, awkwardness and freezing. The main pathophysiology of Parkinson's disease is neurodegeneration of nigrostriatal dopaminergic neurons. Neurotoxins or oxidative stress to the dopaminergic neurons have been discussed as one of the etiologies of degeneration. Antioxidant or neuroprotective agents will be the future drugs for Parkinson's disease. At present, supplement of dopamine by levodopa administration, retarding the metabolism of levodopa or dopamine by a dopa decarboxylase inhibitor (DCI), MAO-B (monoamine oxidase inhibitor type B) inhibitor or catechol-O-methyltransferase (COMT) inhibitor, dopamine receptor agonists, anticholinergic agents, dopamine release enhancer/uptake inhibitor, N-methyl-D-aspartate (NMDA) receptor antagonists are applied for the treatment of Parkinson's disease. New agents such as adenosine receptor antagonists, serotonergic agents and nicotinic receptor agonists are under investigation. Agents to facilitate the growth of nerves or to inhibit degeneration of nerves are also studied and will be developed for the treatment of Parkinson's disease in the future. In the case of familial Parkinson's disease, abnormal genes were identified. Gene therapy might be another future treatment for these cases.

Topics: Amantadine; Animals; Antiparkinson Agents; Aromatic Amino Acid Decarboxylase Inhibitors; Benzophenones; Carbidopa; Catechol O-Methyltransferase Inhibitors; Dopamine Agonists; Enzyme Inhibitors; Genetic Therapy; Humans; Levodopa; Monoamine Oxidase Inhibitors; Nitrophenols; Parkinson Disease; Receptors, N-Methyl-D-Aspartate; Tolcapone

Parkinson's disease is the most common neurodegenerative disease in which the chemical pathology is known and effective symptomatic treatment, levodopa, is available. Therapy in the initial years after initiation with dopa decarboxylase inhibitors, carbidopa or benserazide, combined with levodopa results in favorable, stable responses. However, by 5 years after the initiation of treatment, over two thirds of patients experience motor fluctuations beginning initially with a "wearing-off" effect followed by more complex fluctuations including dyskinesias and "on-off" responses. A number of strategies have been developed in an attempt to deal with these complications including changing doses and frequencies, adding agonist medications, adding or substituting controlled-release levodopa, and surgical therapies. A more recent strategy has centered on increasing the availability of intracellular levodopa and synaptic dopamine by inhibiting the peripheral and central metabolism of levodopa to 3-O-methyldopa with the use of a catechol-O-methyltransferase inhibitor. To date, two of these inhibitors, tolcapone and entacapone, are available to treat the wearing-off phase of levodopa therapy.

Topics: Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Dopamine; Dopamine Agents; Enzyme Inhibitors; Humans; Levodopa; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

Since the introduction of levodopa to treat Parkinson's disease (PD), several new therapies have been directed at improving symptom control, which can decline after a few years of levodopa therapy. Dopaminergic agents can serve as adjuncts or as alternatives to levodopa. In addition, a new class of drugs, catechol-O-methyltransferase inhibitors, can extend the duration of levodopa action. Although surgical options such as pallidotomy offer improvement of parkinsonism beyond the realm of pharmacologic treatment, judicious administration of drugs in combination can generally solve most problems of PD.

Topics: Antiparkinson Agents; Benzophenones; Benzothiazoles; Cabergoline; Catechol O-Methyltransferase Inhibitors; Dopamine Agonists; Drug Synergism; Enzyme Inhibitors; Ergolines; Humans; Indoles; Levodopa; Nitrophenols; Parkinson Disease; Pramipexole; Thiazoles; Tolcapone

Registration of the inhibitor of the catechol-O-methyltransfersase (COMT) tolcapone has been stopped due to the possible relationship of tolcapone treatment to three cases of fatal hepatitis. As a result, strong uncertainty has emerged among neurologists about the principle of COMT inhibition itself. We review data, especially on the remaining COMT inhibitor, entacapone, with regard to pre-clinical and clinical efficacy and safety.

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Clinical Trials as Topic; Dopamine; Humans; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

Catechol-O-methyltransferase (COMT) inhibitors are a new therapeutic option in the treatment of patients with Parkinson's disease. COMT inhibitors act by extending the duration of action of levodopa, thus improving the amount of time a patient can experience benefit from levodopa. COMT inhibitors are only used in conjunction with levodopa. They do have a propensity to augment dopaminergic effects, such that levodopa doses might need to be adjusted downward. Other side effects of COMT inhibitors include diarrhea and liver function abnormalities. Due to the latter, recent guidelines have been developed to monitor patients on tolcapone for this rare side effect, and these guidelines will be discussed. This article also provides representative case histories for the appropriate use of COMT inhibitors that illustrate how these drugs can be used to manage patients with a fluctuating response to levodopa.

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Drug Synergism; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Nitrophenols; Parkinson Disease; Patient Selection; Tolcapone

During the last half of the 20th century, medical treatment for Parkinson's disease (PD) showed remarkable progresses, resulting in marked prolongation of life and self-dependency of patients. In Japan, peak of ages of PD patients visiting all medical institutions was between 75 and 84 years of age(1993), with which course of illness is predicted to exceed twenty years in a large number of patients. As exploration of neuroprotective therapies for PD has not been successful yet, continuous progress in neuronal cell death in the substantia nigra result in loss of efficacy of medication, motor fluctuations and CNS side effects such as dyskinesia and psychosis in the long course of dopaminergic supplementation therapies. Future development of medical therapies for PD is expected in different ways. First, elaboration in controlled-release of DCI/levodopa, utilization of dopamine(DA) receptor agonists with different profiles in affinity to DA receptor subtypes and half-time of blood concentration, and utilization of COMT inhibitors. Second, neuroprotection with MAO-B inbitators or DA receptor agonists. Neuroprotective function is expected in animal studies for these substances but clinical usefulness should be verified with randomised controlled trials. Third, treatment for extra-motor symptoms such as dementia, cognitive disorders, depression, autonomic disturbances such as orthortatic hypotension and bladder disturbances, which is essential for maintenance of quality of life of patients with long course of illness. Gene therapy, neuroprotection before development of symptoms in PD may be attained within the first few decades of the next century. In this respect, establishment of preclinical diagnosis with neuroimaging and sensitive motor and psychological tests is imperative.

Topics: Animals; Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Dopamine Agonists; Drug Therapy; Forecasting; Genetic Therapy; Humans; Levodopa; Monoamine Oxidase Inhibitors; Nerve Growth Factors; Nitrophenols; Parkinson Disease; Quality of Life; Tolcapone

Levodopa is the most efficacious drug in the symptomatic treatment of Parkinson's disease. However, exogenously administered levodopa is extensively metabolized in the periphery by aromatic amino acid decarboxylase (AAAD) and catechol-O-methyltransferase (COMT) so that only 1% of an administered dose gains access to the brain. Even when levodopa is co-administered with an inhibitor of AAAD such as benserazide or carbidopa, the bulk (90%) of levodopa is converted by COMT to the therapeutically inactive 3-O-methyldopa. Two COMT inhibitors, tolcapone and entacapone, have recently been introduced as adjuncts to levodopa to further inhibit peripheral levodopa metabolism and thereby enhance brain levodopa availability. This paper reviews the pharmacokinetics, dosing schedule, peripheral and central effects, and safety profile of these agents.

Topics: Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Humans; Levodopa; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

This paper reviews the issue of hepatotoxicity with the use of the catechol-O-methly transferase (COMT) inhibitors tolcapone and entacapone. Neither drug caused hepatotoxicity in preclinical toxicity testing. However, in clinical trials of tolcapone, liver chemistry tests were elevated more than 3 times above the upper limit of normal in approximately 1% of patients who took the 100 mg dose and in approximately 3% of patients who took the 200 mg dose. These observations led to the recommendation that periodic monitoring of liver function be performed. Post-marketing surveillance studies noted 3 instances of acute liver failure with death after 60,000 patients had received tolcapone for a total of 40,000 patient-years. For this reason, the drug was withdrawn from the market in Europe and Canada, and a black box warning issued in the United States. In contrast, clinical trials with entacapone demonstrated no increase in liver enzymes above those observed with placebo. Further, no instances of acute liver failure or death attributed to the drug have been observed in post-marketing surveillance studies. Consequently, liver monitoring is not required with this agent. These data demonstrate that tolcapone is associated with a risk of hepatotoxicity but that no such risk has been detected with entacapone.

Topics: Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Humans; Liver; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

Two inhibitors of catechol-O-methyl transferase (COMT), tolcapone and entacapone, have recently been introduced as adjuncts to levodopa in the treatment of Parkinson's disease patients. Both have been shown to provide PD patients with increased "on" time, decreased "off" time, and improved motor scores. There are, however, a number of practical issues that must be considered in order to achieve maximal benefits with this class of agent. They include dosing and administration, efficacy, adverse events, and patient education. In general, these agents are easy to administer and well tolerated. Both the benefits and the principal side effects of treatment are related to increased dopaminergic activity. Patients must be advised of possible side effects so that they can be reported in a timely manner. Physicians must appreciate that dopaminergic side effects, such as dyskinesia, should be controlled by adjusting the dose of levodopa and not the COMT inhibitor. Explosive diarrhea has been reported with tolcapone and usually necessitates discontinuing the drug. Tolcapone must also be monitored for possible liver dysfunction. This has not been reported with entacapone, and no monitoring is required. Metabolites of tolcapone and entacapone may cause discoloration of the urine. This is harmless but patients should be advised that this may occur.

Topics: Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Humans; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

Catechol-O-methyl transferase (COMT) inhibitors block the peripheral metabolism of levodopa, increase its plasma half-life, and enhance its brain availability. Two COMT inhibitors, tolcapone and entacapone, have recently been made available as adjunctive agents to levodopa. In PD patients with motor fluctuations, they have been shown to increase "on" time and reduce "off" time. In patients with more advanced disease, they provide similar benefits, but patients tend to experience less overall benefit and a greater likelihood of developing dopaminergic adverse events. Accordingly, closer monitoring is required. In stable patients who have not yet developed motor complications, there are preliminary data suggesting that they experience improvements in motor function and in activities of daily living. Finally, there are theoretical reasons to consider administering a COMT inhibitor to patients from the onset of levodopa therapy in order to reduce the likelihood that motor complications will develop. COMT inhibitors are easy to administer, do not require titration, and are generally well tolerated particularly in patients with relatively mild disease. Adverse events are primarily dopaminergic and can usually be controlled by levodopa dose adjustments. COMT inhibitors have thus proven to be a useful addition to the therapeutic armamentarium of PD.

Topics: Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Humans; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

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.

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase; Clinical Trials as Topic; Drug Interactions; Enzyme Inhibitors; Humans; Levodopa; Multicenter Studies as Topic; Nitrophenols; Parkinson Disease; Tolcapone

Despite advances in the treatment of PD, there remain significant unmet therapeutic needs. This is particularly true at the later stages of the disease when dopaminergic therapy is complicated by motor fluctuations and dyskinesias. Inhibition of dopamine metabolism is a valuable adjunct to exogenous dopaminergic replacement. Inhibitors of MAO-B have been used to treat early and advanced PD for a number of years. Although controversy remains, existing evidence still raises the possibility that MAO-B inhibition may confer a protective effect in PD, delaying the progression of the underlying pathology. More recently, clinically useful inhibitors of COMT have become available. These medications largely act peripherally to increase the pool of available dopamine precursor and prolong the duration of effect of L-dopa. They are indicated primarily for control of motor fluctuations.

Topics: Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Dopamine; Enzyme Inhibitors; Humans; Monoamine Oxidase Inhibitors; Nitriles; Nitrophenols; Parkinson Disease; Randomized Controlled Trials as Topic; Selegiline; Tolcapone

Topics: Adverse Drug Reaction Reporting Systems; Antiparkinson Agents; Benzophenones; Chemical and Drug Induced Liver Injury; Drug-Related Side Effects and Adverse Reactions; European Union; Humans; Legislation, Drug; Nitrophenols; Parkinson Disease; Tolcapone

Several new methods for the treatment of patients suffering from Parkinson's disease have been introduced during the last few years. COMT inhibitors are available in addition to levodopa with a decarboxylase inhibitor. COMT inhibitors enhance and prolong the effect of single levodopa doses. Severe side effects have been mentioned in connection with the COMT inhibitor tolcapone in recent months. Several new dopaminergic agonists now provide efficacious monotherapy in the early stages of the disease. This brings about a reduction in late problems of treatment such as dyskinesias and fluctuations. Stereotaxic operations in the pallidum and the subthalamic afford relief for these late complications of treatment in selected patients.

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Dopamine Agonists; Drug Therapy, Combination; Humans; Levodopa; Nitrophenols; Parkinson Disease; Stereotaxic Techniques; Thalamic Nuclei; Tolcapone

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Enzyme Inhibitors; Humans; Nitrophenols; Parkinson Disease; Tolcapone

Movement disorders is a term applied for a heterogeneous group of diseases and syndromes sharing deficits of voluntary motor function or movement patterns. In clinical practice, the term movement disorders is usually employed to designate those syndromes and diseases that are linked to a pathology or dysfunction of cortico-basal ganglia circuits. The last years have witnessed a rapid expansion in our understanding of the etiological and pathophysiological factors underlying movement disorders such as Parkinson's disease or dystonia. The discovery of new gene mutations is bound to give rise to new insights into the molecular pathogenesis of movement disorders related to neurodegenerative processes. It is already becoming apparent that pathological protein aggregation may be a common link in the neuronal degeneration underlying such diverse entities as spinocerebellar ataxia, idiopathic torsion dystonia and Parkinson's disease. So far, these new findings have not been translated into new forms of symptomatic or preventive therapies. Nevertheless, symptomatic treatment of movement disorders, as evident in the field of Parkinson's disease, is one of the most rewarding and innovative areas of neurological therapy.

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Dopamine Agonists; Drug Therapy, Combination; Electric Stimulation Therapy; Enzyme Inhibitors; Globus Pallidus; Humans; Movement Disorders; Mutation; Nitriles; Nitrophenols; Parkinson Disease; Subthalamic Nucleus; Tolcapone

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of tolcapone are reviewed. Tolcapone is the first drug brought to market from the new class of selective and reversible inhibitors of catechol-O-methyltransferase. Tolcapone is indicated for use in the treatment of Parkinson's disease as an adjunct to levodopa-carbidopa therapy in patients who are experiencing fluctuations in symptoms and who are not responding to or are not appropriate candidates for other adjunctive therapies. The absolute bioavailability of tolcapone after an oral dose is about 65%. Clinical trials have demonstrated that tolcapone 50-200 mg three times daily reduces "off" time in patients refractory to levodopa-carbidopa, Unified Parkinson's Disease Rating Scale scores, and the dosage of levodopa-carbidopa required for symptom suppression. The most frequent adverse effects of tolcapone are dyskinesia, nausea, sleep disorders, dystonia, orthostatic hypotension, diarrhea, dizziness, and hallucinations; also, there is a potential for elevation of liver transaminase concentrations in the blood. To date, three deaths from fulminant hepatic failure in association with tolcapone have been reported. Extensive liver function testing is required of all patients before and during therapy. The recommended starting dosage is 100 mg orally three times daily as an adjunct to levodopacarbidopa therapy; a concurrent reduction in the levodopa dosage of about 30% is suggested. Patient response should be monitored carefully during the first three weeks of therapy; treatment should be discontinued in patients failing to respond during this initial use. Tolcapone is of benefit in fluctuating Parkinson's disease, but benefits must be carefully weighed against risks in individual patients.

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Drug Interactions; Enzyme Inhibitors; Humans; Nitrophenols; Parkinson Disease; Tolcapone

During the initial stages of Parkinson's disease, treatment with levodopa plus a decarboxylase inhibitor (carbidopa or benserazide) provides adequate control of symptoms. However, as the disease progresses, the clinical response to treatment often begins to fluctuate, becoming increasingly correlated with fluctuations in plasma concentrations of levodopa-the "wearing-off" phenomenon. Many strategies have attempted, with various degrees of success, to increase the availability of levodopa and its active metabolites, thus reducing these fluctuations in response. This review focuses on the role of the new catechol O-methyltransferase (COMT) inhibitors tolcapone and entacapone as adjuncts to levodopa therapy. These agents act effectively and safely to increase the amount of levodopa that is available to enter the brain by extending the half-life of levodopa, resulting in more stable levels in the plasma and prolonging "on" time.

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Drug Therapy, Combination; Enzyme Inhibitors; Half-Life; Humans; Levodopa; Nitriles; Nitrophenols; Parkinson Disease; Psychomotor Performance; Randomized Controlled Trials as Topic; Tolcapone

Catechol O-methyltransferase (COMT) is an important enzyme that is linked directly to therapy with levodopa. Considering the demonstrated mechanism of action and pharmacologic profiles of COMT inhibitors, it is reasonable to hypothesize that these agents would improve the disability associated with Parkinson's disease. Two basic classes of COMT inhibitors are being studied in patients with PD: those that act exclusively extracerebrally or peripherally (e.g., entacapone) and those that cross the blood-brain barrier (e.g., tolcapone). With COMT inhibition, greater peripheral bioavailability of levodopa occurs in humans without an enhancement of peak plasma levels. It is reasonable to suggest that COMT inhibition will be associated with prolonged effects of levodopa in PD, without increased peak dose toxicity in the form of dyskinesias and hallucinations.

Topics: Animals; Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Dopamine Agents; Enzyme Inhibitors; Half-Life; Humans; Levodopa; Nitrophenols; Parkinson Disease; Tolcapone

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.

Topics: Antiparkinson Agents; Benzophenones; Biological Availability; Catechol O-Methyltransferase Inhibitors; Clinical Trials as Topic; Dopamine Agents; Drug Administration Schedule; Drug Therapy, Combination; Enzyme Inhibitors; Half-Life; Humans; Levodopa; Nitrophenols; Parkinson Disease; Tolcapone; Volunteers

Degradation of levodopa in the periphery is known to be associated with motor fluctuations and dyskinesia in Parkinson's disease (PD) patients. The enzyme catechol-O-methyltransferase (COMT) is responsible for much of this degradation. Therefore, inhibiting COMT activity is one method of extending the action of levodopa. The new nitrocatechol-type COMT inhibitors entacapone, nitecapone, and tolcapone inhibit COMT in the periphery; tolcapone also inhibits COMT activity centrally. COMT inhibitors increase patients' duration of response to levodopa and reduce response fluctuations. Administration may prolong levodopa-induced dyskinesia, but peak-dose dyskinesia does not appear to increase. To reduce dyskinesia, the total daily dose of levodopa can be reduced.

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Enzyme Inhibitors; Humans; Levodopa; Nitriles; Nitrophenols; Parkinson Disease; Pentanones; Tolcapone

A new approach in the treatment of Parkinson's disease is the inhibition of catechol-O-methyltransferase (COMT) with new generation COMT inhibitors, entacapone and tolcapone. Entacapone acts mainly peripherally whereas tolcapone acts both peripherally and centrally. They induce a dose-dependent inhibition of COMT activity in erythrocytes and a significant decrease in the plasma levels of 3-O-methyldopa, indicating their effectiveness as COMT inhibitors. Consequently, they increase the elimination half-life of levodopa and thus prolong the availability of levodopa to the brain without significantly affecting the Cmax or tmax of levodopa. Clinically, the improved levodopa availability is seen as prolonged motor response to levodopa/DDC inhibitor and also as prolonged duration of dyskinesias in Parkinson's disease patients with end-of-dose fluctuations. The dyskinesias are managed by decreasing the daily levodopa dose in Parkinson's disease patients with end-of-dose fluctuations. Both pharmacokinetically and clinically the 200-mg dose of entacapone is the most effective dose compared with placebo. For tolcapone 100 and 200 mg have most often proved to be the optimal doses. Based on the duration of COMT inhibition entacapone is administered with each levodopa/DDC inhibitor dose whereas tolcapone is given three times daily. Both entacapone and tolcapone are well-tolerated. However, there seems to be a trend for tolcapone to induce more often diarrhoea and increase in liver transaminases compared with entacapone. Thus, COMT inhibitors are clinically significant and beneficial adjunct to levodopa therapy in Parkinson's disease patients with end-of-dose fluctuations. Their effects and significance also in the treatment of de novo patients need to be clarified.

Topics: Benzophenones; Catechol O-Methyltransferase; Catechols; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Enzyme Inhibitors; Humans; Levodopa; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

Topics: Antiparkinson Agents; Benzophenones; Humans; Nitrophenols; Parkinson Disease; Tolcapone

Topics: Benzophenones; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Humans; Nitrophenols; Parkinson Disease; Tolcapone

To summarize the development, pharmacology, pharmacokinetics, efficacy, and safety of five investigational antiparkinsonian drugs that are in or have recently completed Phase III trials: three dopamine agonists, pramipexole, ropinirole, and cabergoline; and two catechol-O-methyltransferase (COMT) inhibitors, entacapone and tolcapone. The pathophysiology and the role of dopamine in Parkinson's disease are also reviewed.. A MEDLINE search of relevant English-language literature, clinical studies, abstracts, and review articles pertaining to Parkinson's disease was conducted. Manual searches of 1996/1997 meeting abstracts published by the American Academy of Neurology and the Movement Disorders Society were also performed. Manufacturers provided unpublished Phase III trial efficacy and pharmacokinetic data.. Clinical trial investigations selected for inclusion were limited to human subjects. Interim analyses after 6 months for long-term clinical studies in progress were included. Pharmacokinetic data from animals were cited if human data were unavailable. Statistical analyses for all studies were evaluated.. By selectivity targeting D2 receptors, the newer dopamine agonists (i.e., cabergoline, pramipexole, ropinirole) may delay the introduction of levodopa and thus the occurrence of levodopa-induced dyskinesias. In addition, they are efficacious as adjunctive therapies in patients with advanced Parkinson's disease. Unlike the currently available dopamine agonists, pramipexole and ropinirole are non-ergot derivatives and do not cause skin inflammation, paresthesias, pulmonary infiltrates, or pleural effusion. The COMT inhibitors, tolcapone and entacapone, improve the pharmacokinetics of levodopa by preventing its peripheral catabolism and increasing the concentration of brain dopamine; thus, these agents may reduce the incidence of "wearing-off" effects associated with the short half-life of levodopa and the progression of Parkinson's disease.. Interim 6-month analyses of pramipexole, ropinirole, and cabergoline for symptomatic treatment of early Parkinson's disease have shown these drugs to be efficacious and relatively well-tolerated when used as monotherapy. Their role in delaying the development of motor fluctuations and delaying the addition of levodopa is the subject of long-term clinical studies. In advanced stages of Parkinson's disease, these medications were also efficacious; however, the main adverse effects included dyskinesias, somnolence, and hallucinations. The COMT inhibitors, entacapone and tolcapone, have also demonstrated efficacy in improving on-time in patients with stable disease. Tolcapone has also demonstrated efficacy in patients with motor fluctuations. Both drugs are relatively well-tolerated, with the exception of dyskinesias that require reduction of the levodopa dosage and occasional diarrhea.

Topics: Benzophenones; Benzothiazoles; Cabergoline; Catechol O-Methyltransferase Inhibitors; Catechols; Dopamine Agonists; Enzyme Inhibitors; Ergolines; Humans; Indoles; Nitriles; Nitrophenols; Parkinson Disease; Pramipexole; Receptors, Dopamine D2; Thiazoles; Tolcapone

New medications recently developed for treating Parkinson's disease include two inhibitors of catechol-O-methyltransferase (COMT), entacapone and tolcapone, which, by decreasing the elimination of levodopa, extend the duration of its effects. Increased 'on' time and less 'wearing-off' symptomatology can be expected with the use of these COMT inhibitors. Two non-ergot dopaminergic agonists (pramipexole and ropinirole) and a long-acting ergoline (cabergoline) are also being introduced. These dopaminergic agonists, like the ergot derivatives currently available (bromocriptine, lisuride, and pergolide), are useful as adjuncts to levodopa, and are also efficacious as monotherapies.

Topics: Antiparkinson Agents; Benzophenones; Benzothiazoles; Cabergoline; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Enzyme Inhibitors; Ergolines; Guidelines as Topic; Humans; Indoles; Nitriles; Nitrophenols; Parkinson Disease; Pramipexole; Thiazoles; Tolcapone; Treatment Outcome

Two novel reversible enzyme inhibitors involved in monoamine metabolism are described. The novel and reversible inhibitors are the catechol-O-methyl-transferase (COMT) inhibitors, Ro 40-7592 (3,4-dihydroxy-4'-methyl-5-nitrobenzophenone), and the monoamine oxidase type-B (MAO-B) inhibitor, Ro 19-6327 (N-(2-aminoethyl)-5-chloro-2-pyridine carboxamide HC1). These may be of special therapeutic benefit in Parkinson's and Alzheimer's diseases.

Topics: Aging; Alzheimer Disease; Benserazide; Benzophenones; Catechol O-Methyltransferase Inhibitors; Drug Combinations; Enzyme Inhibitors; Humans; Levodopa; Monoamine Oxidase Inhibitors; Nitrophenols; Parkinson Disease; Picolinic Acids; Tolcapone

Catechol-O-methyltransferase inhibitors may be used to decrease levodopa requirement. The objective was to investigate whether the levodopa/carbidopa intestinal gel infusion dose can be reduced by 20% without worsening of motor fluctuations and levodopa concentration stability when oral catechol-O-methyltransferase inhibitors are added.. A short-term, randomized, partly blinded, crossover, investigator-initiated clinical trial was performed, with levodopa/carbidopa intestinal gel combined with oral entacapone and tolcapone on two different days in 10 patients. The primary outcome measure was difference in coefficient of variation of levodopa in plasma between levodopa/carbidopa, levodopa/carbidopa/entacapone, and levodopa/carbidopa/tolcapone. The secondary outcome measures other pharmacokinetic variables, patient-reported outcome, and blinded analysis of motor performance.. Variation of plasma levodopa concentrations did not differ significantly between the treatments. The treatments did not differ regarding motor performance. Levodopa concentrations were significantly higher using tolcapone. Concentrations of the metabolite 3-O-methyldopa decreased gradually during catechol-O-methyltransferase inhibition.. According to this small, short-term pilot study, oral catechol-O-methyltransferase inhibitors administered in 5-h intervals may be useful in cases where levodopa/carbidopa intestinal gel dose reduction is wanted. Stability of plasma levodopa levels is not significantly altered, and off-time is not increased when decreasing the levodopa/carbidopa intestinal gel dose by 20%. Rather, the dose should probably be decreased more than 20%, especially under tolcapone co-treatment, to avoid increased dyskinesias with time.

Topics: Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Benzophenones; Catechols; Cross-Over Studies; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Nitrophenols; Parkinson Disease; Pilot Projects; Self Report; Single-Blind Method; Sweden; Tolcapone; Tyrosine

The aims of the present study were to investigate the pharmacokinetic and pharmacodynamic (pk/pd) relationship of levodopa (l-dopa) in patients with advanced Parkinson disease (PD) and also to evaluate the effect of tolcapone on the pk/pd analysis of l-dopa in 1 patient with severe dyskinesias and fluctuations.. The pharmacokinetics (plasma concentrations of l-dopa and 3-O-methyldopa [3-OMD]) and motor effects (global score of the Unified Parkinson's Disease Rating Scale-III) of a single dose of l-dopa (plus the peripheral decarboxylase inhibitor 1:4) were determined in 14 patients with advanced PD. Patients were classified into 2 groups according to Hoehn and Yahr scale (stages 2 and 3). In 1 patient with severe dyskinesias and fluctuations, pk/pd of l-dopa were evaluated before and after coadministration of tolcapone at 100 mg 2 times daily for 1 month. The pk/pd analysis was based on an estimate of the maximal response model with a semiparametric approach to effect site equilibrium.. The highest levels of l-dopa and 3-OMD were observed in patients with stage 3 of Hoehn and Yahr scale. We showed differences in the pk/pd parameters after coadministration of tolcapone in 1 patient as well as the clinical improvement.Univariate analysis showed some significant correlations (P < 0.05) between l-dopa pk/pd parameters and patients' age, duration of l-dopa treatment, and duration of the disease. Multivariate analysis adjusted for patients' age, sex, duration of the disease, and Hoehn and Yahr stage showed that presence of diphasic (dyskinesia-improvement-dyskinesia [DID]) dyskinesias was the only independent predictor of larger threshold level - EC50 (mean concentration at half maximal effect) of l-dopa (P = 0.034).. The motor complications during long treatment therapy in patients with advanced PD especially with stage 3 Hoehn and Yahr scale were correlated to the higher plasma concentrations of l-dopa. In the presented study, patients with motor complications, especially with DID dyskinesias, exhibited a larger threshold level (EC50). The clinical improvement of a patient who received l-dopa and tolcapone can be explained by tolcapone-induced changes of peripheral and central l-dopa pharmacokinetics, which led to a decrease of l-dopa EC50 and 3-OMD concentrations. Our data indicate that pk/pd analysis may be helpful for monitoring the efficiency of therapeutic strategy applied in PD patients.

Topics: Age of Onset; Aged; Antiparkinson Agents; Aromatic Amino Acid Decarboxylase Inhibitors; Benserazide; Benzophenones; Carbidopa; Catechol O-Methyltransferase Inhibitors; Drug Combinations; Drug Therapy, Combination; Dyskinesias; Enzyme Inhibitors; Female; Half-Life; Humans; Levodopa; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Nitrophenols; Parkinson Disease; Severity of Illness Index; Tolcapone; Tyrosine

To examine changes in quality of life (QOL) and global clinical status after 30 days of adjunctive treatment with tolcapone, a revers-ible inhibitor of catechol-O-methyltransferase, in patients with fluctuating Parkinson's disease.. This 30-day, multicenter, open-label, community-based study enrolled fluctuating Parkinson's disease patients to receive tolcapone 100 mg TID as an adjunct to levodopa/carbidopa. The primary end point was QOL change assessed using the Parkinson's Disease Questionnaire (PDQ)-8. Clinical change was assessed using the investigator-rated Clinical Global Impression of Improvement Scale (CGI-I).. Fifty-six physicians enrolled 202 patients; 138 (68%) were > or = 65 years of age and 116 (57%) had Parkinson's disease for > or = 5 years. The mean PDQ-8 total score improved from 42.1 to 34.8 after 30 days of tolcapone (P<.0001). Sixty-nine percent of patients improved on the CGI-I. Physicians planned to continue tolcapone beyond the 30 days in 72%, most commonly because of positive changes in motor function and overall general improvement. No patient discontinued because of liver adverse events.. Adjunctive tolcapone treatment was associated with statistically significant improvement in QOL in fluctuating Parkinson's disease patients. A majority of patients experienced clinical benefits and continued treatment beyond the end of this study. No liver-related adverse events were reported.

Topics: Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Benzophenones; Female; Humans; Levodopa; Male; Middle Aged; Nitrophenols; Parkinson Disease; Quality of Life; Residence Characteristics; Severity of Illness Index; Surveys and Questionnaires; Tolcapone; United States; Young Adult

This study investigated the feasibility, safety, and potential benefit in motor symptom control when switching from a dopamine agonist to tolcapone as an adjunctive therapy in patients with Parkinson's disease with a fluctuating response to levodopa (l-dopa). We determined the efficacy of 2 replacement strategies.. In this 10-week, randomized, open-label, stratified, parallel-group trial, 150 patients on a stable regimen of l-dopa/decarboxylase inhibitor in combination with bromocriptine, lisuride, or pergolide were switched to tolcapone. Primary end point was the change in daily "off" time from baseline to the end of week 10 as assessed by patient "on-off" diaries. Patients had their respective dopamine agonist reduced and finally withdrawn either by day 6 (short-term replacement, n = 72) or by day 23 (long-term replacement, n = 78).. At week 10, a significant reduction from baseline in daily "off" time (-15.9 +/- 19.3%; P < 0.001) and a significant increase of "on" time (14.6 +/- 19.8%; P < 0.001) were observed. Other efficacy variables (Unified Parkinson's Disease Rating Scale II, III, and IVb and Investigator's Global Assessment scores) improved significantly after switching to tolcapone. In general, there was no significant difference between the 2 replacement strategies. Treatment was better tolerated after the switch to tolcapone according to the IGA of tolerability.. Tolcapone, in principle, seems to be an alternative adjunct for patients, who fail to receive sufficient benefit from a dopamine agonist, for example, in case they do not tolerate an increase in dose or have unacceptable side effects. The switch from a dopamine agonist to tolcapone can be done safely within a few days.

Topics: Aged; Ambulatory Care Facilities; Aromatic Amino Acid Decarboxylase Inhibitors; Benserazide; Benzophenones; Carbidopa; Catechol O-Methyltransferase Inhibitors; Dopamine Agonists; Drug Combinations; Drug Therapy, Combination; Dyskinesias; Enzyme Inhibitors; Feasibility Studies; Female; Humans; Levodopa; Male; Middle Aged; Nitrophenols; Parkinson Disease; Severity of Illness Index; Time Factors; Tolcapone; Treatment Outcome

This double-blind study examined the efficacy and safety of replacing entacapone with tolcapone in fluctuating Parkinson's disease (PD) patients. Patients receiving entacapone for > or =15 days were randomly assigned to continue entacapone (n = 75) or switch to tolcapone (n = 75) and were followed up for 3 weeks. Efficacy measures included changes in on time (without disabling dyskinesia) and an investigator's global assessment (IGA). The on time increased by > or =1 hour/day (primary efficacy measure) in 43% of entacapone-treated patients and 53% of tolcapone-treated patients, and by > or =3 hours/day in 13% and 25%, respectively. The IGA indicated moderate/marked improvements in 25% of entacapone patients and 39% receiving tolcapone. Response rates (the proportion of patients with > or =1 hour/day increase in on time and improvements on IGA) were 17% with entacapone and 32% with tolcapone. Dyskinesia was the most common adverse event affecting 29% of entacapone and 31% of tolcapone recipients. One patient in each group had elevated liver enzymes, resulting in treatment withdrawal (levels returned to normal thereafter in both cases). In conclusion, within the limits of the protocol, there was a tendency for tolcapone to offer enhanced efficacy in patients with fluctuating PD, despite optimized entacapone therapy. Tolcapone can be considered, therefore, for patients whose motor fluctuations are inadequately controlled by their existing regimen.

Topics: Aged; Antiparkinson Agents; Benzophenones; Case-Control Studies; Catechols; Cross-Over Studies; Double-Blind Method; Drug Tolerance; Female; Follow-Up Studies; Humans; Male; Middle Aged; Nitriles; Nitrophenols; Parkinson Disease; Prospective Studies; Tolcapone; Treatment Outcome

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

Topics: Adult; Aged; Aged, 80 and over; Alanine Transaminase; Antiparkinson Agents; Aspartate Aminotransferases; Benzophenones; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Nitrophenols; Parkinson Disease; Tolcapone

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.. 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.. 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).. 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.

Topics: Aged; Aged, 80 and over; Antiparkinson Agents; Aromatic Amino Acid Decarboxylase Inhibitors; Benzophenones; Catechol O-Methyltransferase Inhibitors; Enzyme Inhibitors; Female; Homocysteine; Humans; Levodopa; Male; Middle Aged; Nitrophenols; Parkinson Disease; Prospective Studies; S-Adenosylhomocysteine; Tolcapone

Topics: Aged; Antiparkinson Agents; Benzophenones; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Nitrophenols; Parkinson Disease; Severity of Illness Index; Tolcapone

Dopamine receptors agonists and catechol-O-methyltransferase (COMT) inhibitors are the novel classes of the drugs for Parkinson's disease (PD) treatment in both early and late stages. In the latter one, there is an increase of substantia nigra neurons degeneration, striatum denervation, changes of dopamine receptors state, dysregulation of Levadopa uptake, dopamine synthesis and storage, decrease of dopamine receptors density in striatum that results in clinical picture alteration and development of pharmaco-therapeutic side-effects, as well as motor fluctuations and drug diskinesias. The use of dopamine receptors agonists and COMT inhibitors at the late PD stages in combination with other antiparkinsonian medications allows improving pharmaco-therapeutic efficacy, along with patient's daily activity and quality of life.

Topics: Activities of Daily Living; Benzophenones; Benzothiazoles; Catechol O-Methyltransferase Inhibitors; Catechols; Dopamine Agonists; Drug Therapy, Combination; Enzyme Inhibitors; Female; Humans; Male; Middle Aged; Nitriles; Nitrophenols; Parkinson Disease; Pergolide; Pramipexole; Quality of Life; Thiazoles; Tolcapone; Treatment Outcome

We have previously designed and validated a 10-item bilingual questionnaire, the Parkinson's Impact Scale (PIMS), as a disease-specific instrument to measure the impact of Parkinson's disease (PD) on the quality of life of patients with PD. In this paper we extend the psychometric assessment of PIMS to a new set of patients, in the context of a cross-over trial by Hoffman-La Roche Ltd, comparing two doses of tolcapone in 116 PD patients who had developed wearing off effect on levodopa. Using data from this trial, we evaluate PIMS' test-retest reliability, construct validity, sensitivity and responsiveness to change. Validation is carried out by correlating the PIMS scores with corresponding UPDRS subscales and with the Schwab and England scale. We show that PIMS has excellent psychometric properties, and can therefore be used not only in clinical trials but also to identify quickly potential problems in major subjective areas of PD patients' lives, in order to refer them effectively to appropriate providers of assistance.

Topics: Antiparkinson Agents; Area Under Curve; Benzophenones; Cross-Over Studies; Humans; Nitrophenols; Parkinson Disease; Psychometrics; Quality of Life; Reproducibility of Results; Tolcapone

Tolcapone is a potent, selective, and reversible inhibitor of cathecol-O-methyl-transferase (COMT). This enzyme plays a crucial role in the extraneural inactivation of catecholamine neurotransmitters. Tolcapone's ability to inhibit central COMT in humans at therapeutic concentrations is not yet clear. The aim was to determine the effect of tolcapone on central COMT activity in Parkinson's disease (PD) using (18)F-dopa positron emission tomography (PET). The study was a randomized two-way crossover study. Twelve PD patients were recruited. On the treatment days patients were given either tolcapone (200 mg) or placebo together with levodopa/carbidopa (100/125 mg) 1 h before the injection of (18)F-dopa. Data were acquired in 25 frames over 94 min for the first PET scan period. At the end of this period the patients were removed from the scanner for 90 min and subsequently repositioned and data acquired in six 10-min time frames over 60 min. Influx constants (Ki) were computed using a graphical approach with a plasma input function. Mean (18)F-dopa putamen Ki's for the first 30-90 min, primarily reflecting central dopa decarboxylase (DDC) activity, were similar in PD patients whether tolcapone was present (0.0078 +/- 0.0031 min(-1)) or absent (0.0078 +/- 0.0030 min(-1)). Mean putamen Ki values calculated 180-240 min after injection of (18)F-dopa, reflecting both central DDC and COMT activity, were unchanged from 30-90' values in the presence of tolcapone (0.0079 +/- 0.0030), implying blockade of central COMT, but were significantly reduced (0.0059 +/- 0.0028) in the absence of this drug. These findings are compatible with clinical doses of tolcapone having a significant blocking effect on peripheral and central COMT but not DDC activity in PD.

Topics: Aged; Benzophenones; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Caudate Nucleus; Cross-Over Studies; Dihydroxyphenylalanine; Dopamine; Enzyme Inhibitors; Humans; Middle Aged; Neostriatum; Neurons; Nitrophenols; Parkinson Disease; Putamen; Tolcapone; Tomography, Emission-Computed

To determine the therapeutic effect of levodopa/benserazide and tolcapone on gait in patients with advanced Parkinson's disease.. Instrumental gait analysis was performed in 38 out of 40 patients with wearing-off phenomenon during a randomized, double-blind, placebo-controlled trial of tolcapone.. Gait analysis disclosed a significant improvement by levodopa/benserazide in walking speed, stride length and the range of motion of hip, knee and ankle joints. At the end of the study, both the UPDRS motor scores during off-period and the percentage of off time improved significantly using tolcapone. However, gait analysis could not confirm this improvement. With respect to levodopa/benserazide effect, the reduction in rigidity correlated with improved angular excursion of the ankle, whereas the decreased bradykinesia correlated with improved stride length and angular excursion of the hip and knee joints.. The results of our gait analysis confirmed that in parkinsonian patients with fluctuating motor symptoms levodopa/benserazide, but not tolcapone, produced a substantial improvement.

Topics: Aged; Antiparkinson Agents; Benzophenones; Biological Availability; Double-Blind Method; Female; Gait; Half-Life; Humans; Levodopa; Male; Nitrophenols; Parkinson Disease; Tolcapone

To investigate the effect of administration of the catechol-Omethyltransferase (COMT) inhibitor tolcapone on the concentration-effect relationship of levodopa in patients with advanced Parkinson's disease and on-off fluctuations.. Nonblind single-group 2-period pharmacokinetic-pharmacodynamic study.. 12 patients, mean age 59 years, with idiopathic Parkinson's disease and response fluctuations.. The pharmacokinetics [plasma concentrations of levodopa and 3-O-methyldopa (3-OMD)] and motor effects [global score of the Columbia University Rating Scale (CURSsigma)] of levodopa (plus the peripheral decarboxylase inhibitor benserazide 1:4) were determined for 4 consecutive dosage intervals (4 hours each, starting at 8.00am) in 12 patients before (day 1) and during (day 8) coadministration of tolcapone 100 mg 3 times daily for 7 days.. Under tolcapone, exposure to levodopa [area under the plasma concentration-time for the dosage interval (AUCt)] observed for the separate doses increased by 1.6- to 2.2-fold, and peak plasma drug concentrations (Cmax) increased by 1.1 - to 2.1 -fold. 3-OMD concentrations at day 8 were reduced to about 20% of the values at day 1. At baseline (day 1, before the first levodopa dose), CURSsigma averaged 40 +/- 10 points. After the first levodopa dose. CURSsigma declined to 20 +/- 9 points. At day 8. the predose CURSsigma decreased to a final score of 31 +/-13 points, and the maximal decline after the first levodopa dose was to a final score of 16 +/- 8 points. Population analysis (NONMEM) of the concentration-effect relationship of levodopa according to a sigmoidal Emax model and over all dosage intervals did not show differences in levodopa responsiveness with or without tolcapone. The population mean of the 50% effective concentration (EC50) of levodopa was 1350 microg/L with an standard error of the population parameter estimate of 18%: adding tolcapone treatment as a covariate did not significantly change the population fit. Circadian influences on levodopa respon- siveness were not evaluable by the NONMEM model due to overparametrisation, but visual inspection of plotted data did not suggest differences in the concentration-effect relationship between the 4 consecutive dosage intervals on days 1 and 8.. The gain in clinical improvement with levodopa under tolcapone can be fully explained by tolcapone-induced changes of peripheral levodopa pharmacokinetics. We suggest that this interaction study, performed in patients and using clinical data, excludes any central effects of tolcapone or any inhibiting effect of 3-OMD on levodopa permeation through the blood-brain barrier, which otherwise would have led to a decrease in the EC50 of levodopa.

Topics: Aged; Area Under Curve; Benzophenones; Catechol O-Methyltransferase Inhibitors; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Nitrophenols; Parkinson Disease; Tolcapone

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.

Topics: Antiparkinson Agents; Benzophenones; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Nitrophenols; Parkinson Disease; Pergolide; Quality of Life; Tolcapone; Treatment Outcome

To use pharmacostatistical models to characterize tolcapone's pharmacokinetics in parkinsonian patients, and to identify any demographic subpopulations which may be at risk of either under- or over-exposure to this catechol-O-methyltransferase (COMT) inhibitor.. Four hundred and twelve patients participated in three multicentre, parallel, double-blind, placebo-controlled, dose-finding studies and received either placebo or tolcapone (50, 200 or 400 mg three times daily) in addition to levodopa/decarboxylase inhibitor therapy. Sparse blood samples were obtained from 275 patients for tolcapone assay and the concentrations (1414 in total) were analysed using the NONMEM program.. The pharmacokinetic model which best described the data was a two-compartment open model with first-order absorption and possibly a lag-time. Tolcapone pharmacokinetics were shown to be stable, with no systematic trend between 2 and 6 weeks of treatment. The absorption of the drug was shown to be rapid and concomitant food intake had only a minor effect on the relative bioavailability (10-20% reduction compared with fasting). The overall clearance of tolcapone could be estimated with good precision (approximately 4. 5-5 l h-1 ), and none of the investigated covariates (e.g. sex, age, body weight) had any clinically significant influence on this parameter. The volume of distribution showed relatively high variability and was calculated to be approximately 30 l, leading to an estimated half-life in patients of approximately 5-8 h.. Using sparse concentrations and mixed effect-effects modelling analysis it is possible to describe the pharmacokinetics of tolcapone in parkinsonian populations. The parameter estimates obtained agreed with those obtained from conventional pharmacokinetic studies and no subpopulation was shown to be at risk of either under- or over-exposure to tolcapone.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Antiparkinson Agents; Area Under Curve; Benserazide; Benzophenones; Carbidopa; Catechol O-Methyltransferase Inhibitors; Enzyme Inhibitors; Female; Humans; Levodopa; Male; Middle Aged; Models, Statistical; Nitrophenols; Parkinson Disease; Population; Risk Factors; Single-Blind Method; Tolcapone

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.

Topics: Aged; Aged, 80 and over; Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Female; Humans; Levodopa; Male; Middle Aged; Nitrophenols; Parkinson Disease; 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.

Topics: Adaptation, Psychological; Adult; Aged; Antiparkinson Agents; Benzophenones; Carbidopa; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Nitrophenols; Parkinson Disease; Quality of Life; Sick Role; Sickness Impact Profile; Tolcapone; Treatment Outcome

To determine the changes in haemodynamics, tolerability and pharmacokinetics that may occur when a combination of tolcapone and levodopa/carbidopa are given with desipramine.. In a crossover study, 22 healthy subjects received desipramine during two 13-day treatment periods (25 mg t.i.d. for 3 days and 50 mg t.i.d. for 10 days), with a washout period of 10-15 days. Subjects received levodopa/carbidopa (100 mg/25 mg t.i.d. for 5 days, days 9-13) and concomitant, double-blind, randomized treatment with either tolcapone (200 mg t.i.d.) or placebo.. No significant pharmacodynamic and pharmacokinetic interactions occurred between tolcapone and desipramine. Adverse events were predictable based on the known effects of the individual drugs.. Tolcapone can be combined with levodopa/carbidopa and desipramine in patients with Parkinson's disease.

Topics: Adult; Antiparkinson Agents; Benzophenones; Cross-Over Studies; Desipramine; Double-Blind Method; Drug Interactions; Drug Tolerance; Female; Hemodynamics; Humans; Levodopa; Male; Nitrophenols; Parkinson Disease; Tolcapone

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.

Topics: Aged; Antiparkinson Agents; Benzophenones; Bromocriptine; Catechol O-Methyltransferase Inhibitors; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Drug Tolerance; Female; Humans; Levodopa; Male; Middle Aged; Neurologic Examination; Nitrophenols; Parkinson Disease; Tolcapone; Treatment Outcome

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.

Topics: Aged; Antiparkinson Agents; Benserazide; Benzophenones; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Enzyme Inhibitors; Female; Humans; Hydrazines; Levodopa; Male; Middle Aged; Nitrophenols; Parkinson Disease; Time Factors; Tolcapone; Tyrosine

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.

Topics: Adolescent; Adult; Antiparkinson Agents; Benserazide; Benzophenones; Catechol O-Methyltransferase; Chromatography, High Pressure Liquid; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Nitrophenols; Parkinson Disease; Time Factors; Tolcapone

Tolcapone is a novel catechol-O-methyltransferase (COMT) inhibitor used as an adjunct to levodopa/carbidopa or levodopa/benserazide therapy to improve treatment of Parkinson's disease. The aim of the current study was to investigate the potential effect of tolcapone on the pharmacokinetics of carbidopa.. This was an open-label study in 12 parkinsonian patients receiving optimal levodopa/carbidopa therapy and tolcapone 200 mg three times daily for 6 weeks. Blood samples were taken at baseline (i.e. before the first tolcapone intake) and after 1-2 weeks and 6 weeks so that carbidopa pharmacokinetics before and during tolcapone treatment could be assessed.. No changes in any pharmacokinetic parameters of carbidopa were observed. The mean AUC(0,tau) and Cmax values at baseline were 0.39 microg ml-1 h and 0. 14 microg ml-1, respectively. During tolcapone treatment these values were on average 0.35 microg ml-1 h (AUC(0,tau), week 1-2), 0. 34 microg ml-1 h (AUC(0,tau), week 6 and 0.13 microg ml-1 (Cmax, weeks 1-2 and 6). tmax remained unchanged (approx. 2 h).. These results indicate that tolcapone does not affect carbidopa elimination and that no interaction of any clinical relevance occurs between tolcapone and carbidopa.

Topics: Aged; Antiparkinson Agents; Benzophenones; Carbidopa; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Drug Combinations; Drug Interactions; Enzyme Inhibitors; Female; Humans; Levodopa; Male; Middle Aged; Nitrophenols; Parkinson Disease; Tolcapone

The cerebral availability of the peripherally and centrally acting catechol-O-methyltransferase (COMT) inhibitor tolcapone is not known in humans. Therefore, we determined the concentration of tolcapone in cerebrospinal fluid (CSF) of 12 parkinsonian subjects 1-4 h after oral application of 200 mg of the drug. The mean concentration was 56.4+/-35.5 nmol/l (mean +/- SD). This concentration was calculated to cause 75.2+/-15% (mean +/- SD) inhibition of COMT in CSF. Thus, tolcapone efficiently inhibits COMT after crossing the blood-brain barrier in humans.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Benzophenones; Blood-Brain Barrier; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Chromatography, High Pressure Liquid; Enzyme Inhibitors; Female; Humans; Male; Middle Aged; Nitrophenols; Parkinson Disease; Tolcapone

Tolcapone is a potent, selective, reversible inhibitor of COMT. Coadministration of tolcapone with levodopa and a decarboxylase inhibitor prolongs the elimination half-life of levodopa and reduces the formation of 3-0-metildopa in a dose-dependent form. The improvement in the pharmacokinetics of levodopa prolongs the motor effects of levodopa. Clinical studies have shown that the concomitant administration of levodopa and tolcapone is effective on the management of the wearing-off phenomenon. Tolcapone can significantly reduce the off time and increases the total on time while simultaneously reducing levodopa dosage and frequency. Most adverse events are dopaminergic in nature and related to the increase in levodopa bioavailability. Dyskinesias may increase in frequency and severity in patients already having dyskinesias and these may appear for the first time after adding tolcapone in patients at risk. Diarrhoea is the main nondopaminergic adverse event leading to the stop of the drug in less than 10% of cases. Taking into account that tolcapone significantly enhance the action of levodopa, it would be wise to reduce the total daily dose of levodopa at the same time that tolcapone is introduced. No tolerance effect was observed in 12-month studies. Tolcapone can be used with standard or sustained release levodopa, and, when appropriate, in conjunction with dopamine agonists or selegiline.

Topics: Antiparkinson Agents; Benzophenones; Dose-Response Relationship, Drug; Double-Blind Method; Drug Synergism; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Humans; Levodopa; Nitrophenols; Parkinson Disease; Tolcapone; Treatment Outcome

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.

Topics: Administration, Oral; Adult; Antiparkinson Agents; Benzophenones; Biological Availability; Carbidopa; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug Interactions; Humans; Levodopa; Male; Middle Aged; Nitrophenols; Parkinson Disease; Tolcapone

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.

Topics: Aged; Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Dopamine Agents; Double-Blind Method; Drug Therapy, Combination; Enzyme Inhibitors; Female; Humans; Levodopa; Male; Middle Aged; Nitrophenols; Parkinson Disease; Time Factors; Tolcapone; Treatment Outcome

We studied the new catechol-O-methyltransferase inhibitor tolcapone, 100 and 200 mg, three times daily (tid) in a randomized, double-blind, parallel-group trial involving 202 parkinsonian patients who were experiencing the "wearing-off" phenomenon on levodopa therapy. After 3 months, patients receiving tolcapone had a significant decrease in mean daily levodopa dose requirement compared with placebo-treated patients (p < 0.01). In patients treated with tolcapone 200 mg tid, daily "off" time, measured using patient diaries, was reduced from baseline by 3.25 hours; this reduction was significantly different from that seen in the placebo group (p < 0.01). Moreover, the number of daily levodopa intakes was reduced significantly in each tolcapone group compared with placebo (p < 0.01). We found significant improvements in motor function and overall efficacy in the tolcapone groups (p < 0.01). The most frequent adverse events were associated with levodopa treatment. Dyskinesia developed or worsened in 18% of patients receiving placebo, in 51% receiving tolcapone 100 mg tid, and in 64% receiving 200 mg tid, with most cases occurring within the first 30 days of the study. Diarrhea was the most frequent nondopaminergic event, occurring in 14% on placebo, 13% on tolcapone 100 mg tid, and 19% on 200 mg tid. Overall 18% of patients withdrew because of adverse events: 15% on placebo, 17% on tolcapone 100 mg tid, and 22% on 200 mg tid. We conclude that tolcapone as an adjunct offers promise for the relief of the "wearing-off " phenomenon in levodopa-treated parkinsonian patients.

Topics: Aged; Antiparkinson Agents; Benzophenones; Canada; Catechol O-Methyltransferase Inhibitors; Dopamine Agents; Double-Blind Method; Enzyme Inhibitors; Female; Humans; Levodopa; Male; Middle Aged; Nitrophenols; Parkinson Disease; Psychomotor Performance; Tolcapone; United States

More than 50% of patients with Parkinson's disease develop motor response fluctuations (the 'wearing off" phenomenon) after more than five years of levodopa therapy. Inhibition of catechol-O-methyltransferase by tolcapone has been shown to increase levodopa bioavailability and plasma elimination half life, thereby prolonging the efficacy of levodopa.. The primary objective was to evaluate the efficacy of tolcapone in reducing "wearing off" in levodopa treated, fluctuating parkinsonian patients. Secondary objectives included assessment of reduction in levodopa requirements, improvement in patients' clinical status, duration of improvements, and tolerability of tolcapone.. In this multicentre, randomised, double blind, placebo controlled trial, 58 patients received placebo, 60 received 100 mg tolcapone three times daily (tid), and 59 received 200 mg tolcapone tid, in addition to levodopa/benserazide.. After three months with 200 mg tolcapone tid, "off" time decreased by 26.2% of the baseline value, "on" time increased by 20.6% (p < 0.01 vs. placebo), and the mean total daily levodopa dose decreased by 122 mg from the baseline dose of 676 mg (p < 0.01). These responses were maintained up to nine months. With 100 mg tolcapone tid, "off" time decreased by 31.5% (p < 0.05), "on" time increased by 21.3% (p < 0.01), and the mean total daily levodopa dose decreased by 109 mg from the baseline dose of 668 mg (p < 0.05). With 200 mg tolcapone tid, unified Parkinson's disease rating scale motor and total scores were significantly reduced, and quality of life (sickness impact profile) scores were significantly improved. Both dosages were well tolerated. Dyskinesia was the most often reported levodopa induced adverse event. Diarrhoea was the most often reported non-dopaminergic adverse event and the most frequent reason for withdrawal from the study: four patients in the 100 mg tolcapone tid group and six in the 200 mg tid group withdrew because of diarrhoea.. Tolcapone prolongs "on" time in fluctuating parkinsonian patients while allowing a reduction in daily levodopa dosage, thereby improving the efficacy of long term levodopa therapy.

Topics: Aged; Antiparkinson Agents; Benserazide; Benzophenones; Catechol O-Methyltransferase Inhibitors; Diarrhea; Dopamine Agents; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Enzyme Inhibitors; Europe; Female; Humans; Levodopa; Male; Middle Aged; Nitrophenols; Parkinson Disease; Tolcapone; Treatment Outcome

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.

Topics: Administration, Oral; Aged; Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Neurologic Examination; Nitrophenols; Parkinson Disease; Pilot Projects; Selegiline; Tolcapone; Treatment Outcome

To assess the efficacy and tolerability of the catechol-O-methyltransferase inhibitor tolcapone in reducing "off/on" fluctuations in levodopa-treated parkinsonian patients.. A randomized, double-blind, placebo-controlled, parallel-group study.. Fifteen Parkinson disease clinics.. 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.. In addition to their usual levodopa-carbidopa regimen, patients received placebo or tolcapone, 100 or 200 mg, 3 times daily orally for 6 weeks.. Change in daily off/on time.. 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%).. 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.

Topics: Aged; Antiparkinson Agents; Benzophenones; Carbidopa; Catechol O-Methyltransferase Inhibitors; Double-Blind Method; Drug Administration Schedule; Female; Humans; Levodopa; Male; Middle Aged; Nitrophenols; Parkinson Disease; Tolcapone; Treatment Outcome

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.

Topics: Aged; Antiparkinson Agents; Benzophenones; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Levodopa; Male; Middle Aged; Movement; Nitrophenols; Parkinson Disease; Placebos; Tolcapone; Treatment Outcome

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%d 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 useful drug adjunct to levodopa in treating patients with PD with wearing-off phenomena.

Topics: Aged; Antiparkinson Agents; Area Under Curve; Benzophenones; Catechol O-Methyltransferase Inhibitors; Enzyme Inhibitors; Female; Half-Life; Humans; Levodopa; Male; Middle Aged; Nitrophenols; Parkinson Disease; Tolcapone; Tyrosine

Topics: Antiparkinson Agents; Benzophenones; Bromocriptine; Drug Therapy, Combination; Drug Tolerance; Humans; Levodopa; Nitrophenols; Parkinson Disease; Tolcapone

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.

Topics: Activities of Daily Living; Aged; Antiparkinson Agents; Benzophenones; Diarrhea; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Motor Activity; Nitrophenols; Parkinson Disease; Placebos; Sickness Impact Profile; Tolcapone; Treatment Outcome

We studied the new catechol-O-methyltransferase inhibitor tolcapone, 100 and 200 mg, three times daily (tid) in a randomized, double-blind, parallel-group trial involving 202 parkinsonian patients who were experiencing the "wearing-off" phenomenon on levodopa therapy. After 3 months, patients receiving tolcapone had a significant decrease in mean daily levodopa dose requirement compared with placebo-treated patients (p < 0.01). In patients treated with tolcapone 200 mg tid, daily "off" time, measured using patient diaries, was reduced from baseline by 3.25 hours; this reduction was significantly different from that seen in the placebo group (p < 0.01). Moreover, the number of daily levodopa intakes was reduced significantly in each tolcapone group compared with placebo (p < 0.01). We found significant improvements in motor function and overall efficacy in the tolcapone groups (p < 0.01). The most frequent adverse events were associated with levodopa treatment. Dyskinesia developed or worsened in 18% of patients receiving placebo, in 51% receiving tolcapone 100 mg tid, and in 64% receiving 200 mg tid, with most cases occurring within the first 30 days of the study. Diarrhea was the most frequent nondopaminergic event, occurring in 14% on placebo, 13% on tolcapone 100 mg tid, and 19% on 200 mg tid. Overall 18% of patients withdrew because of adverse events: 15% on placebo, 17% on tolcapone 100 mg tid, and 22% on 200 mg tid. We conclude that tolcapone as an adjunct offers promise for the relief of the "wearing-off" phenomenon in levodopa-treated parkinsonian patients.

Topics: Aged; Antiparkinson Agents; Benzophenones; Double-Blind Method; Female; Humans; Male; Middle Aged; Motor Activity; Nitrophenols; Parkinson Disease; Placebos; Tolcapone; Treatment Outcome

More than 50% of patients with Parkinson's disease develop motor response fluctuations (the "wearing off" phenomenon) after more than five years of levodopa therapy. Inhibition of catechol-O-methyltransferase by tolcapone has been shown to increase levodopa bioavailability and plasma elimination half life, thereby prolonging the efficacy of levodopa.. The primary objective was to evaluate the efficacy of tolcapone in reducing "wearing off" in levodopa treated, fluctuating parkinsonian patients. Secondary objectives included assessment of reduction in levodopa requirements, improvement in patients' clinical status, duration of improvements, and tolerability of tolcapone.. In this multicentre, randomised, double blind, placebo controlled trial, 58 patients received placebo, 60 received 100 mg tolcapone three times daily (tid), and 59 received 200 mg tolcapone tid, in addition to levodopa/benserazide.. After three months with 200 mg tolcapone tid, "off" time decreased by 26.2% of the baseline value, "on" time increased by 20.6% (P

Topics: Aged; Antiparkinson Agents; Benzophenones; Biological Availability; Catechol O-Methyltransferase Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Enzyme Inhibitors; Female; Humans; Levodopa; Male; Middle Aged; Nitrophenols; Parkinson Disease; Severity of Illness Index; Tolcapone

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.

Topics: Activities of Daily Living; Aged; Antiparkinson Agents; Benzophenones; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Nitrophenols; Parkinson Disease; Severity of Illness Index; Tolcapone

The aim of this study was to evaluate the effects of Tolcapone, a reversible, selective inhibitor of catechol-O-methyltransferase, on the cognitive function of eight patients with advanced Parkinson's disease. They underwent neuropsychological and motor assessment at baseline and were re-evaluated after 6 months. During this period, they received Tolcapone three times daily, while the L-dopa dosage was progressively reduced. Significant improvements were observed in the attentional task, auditory verbal short-term memory, visuo-spatial recall, constructional praxia and motor symptoms. These data suggest that treatment with Tolcapone, in combination with L-dopa therapy, may determine a significant improvement in cognitive resources of patients with advanced Parkinson's disease.

Topics: Aged; Antiparkinson Agents; Attention; Benzophenones; Catechol O-Methyltransferase Inhibitors; Cognition; Dopamine; Enzyme Inhibitors; Female; Humans; Male; Memory; Middle Aged; Motor Activity; Neuropsychological Tests; Nitrophenols; Norepinephrine; Parkinson Disease; Tolcapone

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.

Topics: Aged; Antiparkinson Agents; Benzophenones; Carbidopa; Catechol O-Methyltransferase Inhibitors; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Neurologic Examination; Nitrophenols; Parkinson Disease; Selegiline; Tolcapone

Tolcapone, a catechol-O-methyltransferase inhibitor, can interfere with the metabolism of levodopa and dopamine and could prolong the motor effect induced by levodopa in parkinsonian patients. To test this hypothesis, we studied the motor effect induced by three acute administrations of a dose of levodopa-benserazide (Madopar) with either 200 mg or 400 mg of tolcapone or placebo, in a double-blind latin-square design. The duration of the on-phase could be compared in 10 parkinsonian patients suffering from square-shaped motor effect. In comparison to placebo, 200 mg and 400 mg of tolcapone significantly increased the mean duration of the on-phase by 61.7 min ( +/- 19.4 SEM) and by 72.2 min ( +/- 18.5), respectively. This clinical effect is suggested to be related mainly to the increase in levodopa area under the curve and half-life induced by tolcapone. The intensity in dyskinesias was increased by 400 mg of tolcapone. Tolcapone appears to be well tolerated and could be helpful as an adjuvant treatment to levodopa in parkinsonian patients with motor fluctuations.

Topics: Aged; Antiparkinson Agents; Benserazide; Benzophenones; Catechol O-Methyltransferase Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Enzyme Inhibitors; Female; Humans; Levodopa; Male; Motor Activity; Nitrophenols; Parkinson Disease; Placebos; Tolcapone

The effects of acute catechol-O-methyltransferase (COMT) inhibition on L-DOPA pharmacokinetics were studied in 10 parkinsonian subjects on stable doses of L-DOPA/carbidopa and selegiline. Tolcapone, a reversible COMT inhibitor, was administered in four single ascending doses (50-800 mg) randomly paired with placebo. Serial plasma concentrations of L-DOPA and its metabolites were measured, and patient diaries and clinical ratings of dyskinesia were completed every 30 min for 6 h. Tolcapone increased the area under the curve of the plasma L-DOPA concentration versus time curve and decreased the accumulation of homovanillic acid. COMT inhibition increased "on" time and the duration of dyskinesia without affecting the maximal amplitude of dyskinesia. Tolcapone may be a useful adjunct to L-DOPA/carbidopa.

Topics: Aged; Antiparkinson Agents; Benzophenones; Carbidopa; Dose-Response Relationship, Drug; Humans; Levodopa; Movement Disorders; Nitrophenols; Parkinson Disease; Selegiline; Tolcapone

Topics: Aged; Benzophenones; Catechol O-Methyltransferase Inhibitors; Double-Blind Method; Drug Synergism; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Nitrophenols; Parkinson Disease; Tolcapone

Two analogues of tolcapone where the nitrocatechol group has been replaced by a 1-hydroxy-2(1

Topics: Benzophenones; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Chelating Agents; Enzyme Inhibitors; Ferric Compounds; Humans; Nitrophenols; Parkinson Disease; Pyridones

Catechol-O-methyltransferase (COMT) plays an important role in the deactivation of catecholamine neurotransmitters and hormones. Inhibitors of COMT, such as tolcapone and entacapone, are used clinically in the treatment of Parkinson's disease. Discovery of novel inhibitors has been hampered by a lack of suitable assays for high-throughput screening (HTS). Although assays using esculetin have been developed, these are affected by fluorescence, a common property of catechol-type compounds. We have therefore evaluated a new homogenous time-resolved fluorescence (HTRF)-based assay from CisBio (Codolet, France), which measures the production of S-adenosyl-L-homocysteine (SAH). The assay has been run in both HTS and medium-throughput screening (MTS) modes. The assay was established using membranes expressing human membrane-bound COMT and was optimized for protein and time to give an acceptable signal window, good potency for tolcapone, and a high degree of translation between data in fluorescence ratio and data in terms of [SAH] produced. pIC50 values for the hits from the HTS mode were determined in the MTS mode. The assay also proved suitable for kinetic studies such as Km,app determination.

Topics: Benzophenones; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; High-Throughput Screening Assays; Humans; Kinetics; Nitrophenols; Parkinson Disease; S-Adenosylhomocysteine; Small Molecule Libraries; Tolcapone

Mutations the in human DJ-1 (hDJ-1) gene are associated with early-onset autosomal recessive forms of Parkinson's disease (PD). hDJ-1/parkinsonism associated deglycase (PARK7) is a cytoprotective multi-functional protein that contains a conserved cysteine-protease domain. Given that cysteine-proteases can act on both amide and ester substrates, we surmised that hDJ-1 possessed cysteine-mediated esterase activity. To test this hypothesis, hDJ-1 was overexpressed, purified and tested for activity towards 4-nitrophenyl acetate (pNPA) as µmol of pNPA hydrolyzed/min/mg·protein (U/mg protein). hDJ-1 showed maximum reaction velocity esterase activity (Vmax = 235.10 ± 12.00 U/mg protein), with a sigmoidal fit (S0.5 = 0.55 ± 0.040 mM) and apparent positive cooperativity (Hill coefficient of 2.05 ± 0.28). A PD-associated mutant of DJ-1 (M26I) lacked activity. Unlike its protease activity which is inactivated by reactive oxygen species (ROS), esterase activity of hDJ-1 is enhanced upon exposure to low concentrations of hydrogen peroxide (<10 µM) and plateaus at elevated concentrations (>100 µM) suggesting that its activity is resistant to oxidative stress. Esterase activity of DJ-1 requires oxidation of catalytic cysteines, as chemically protecting cysteines blocked its activity whereas an oxido-mimetic mutant of DJ-1 (C106D) exhibited robust esterase activity. Molecular docking studies suggest that C106 and L126 within its catalytic site interact with esterase substrates. Overall, our data show that hDJ-1 contains intrinsic redox-sensitive esterase activity that is abolished in a PD-associated mutant form of the hDJ-1 protein.

Topics: Esterases; Humans; Hydrogen Peroxide; Molecular Docking Simulation; Mutation; Nitrophenols; Oxidation-Reduction; Oxidative Stress; Parkinson Disease; Protein Deglycase DJ-1; Reactive Oxygen Species

Subtle cognitive and behavioral changes are common in early Parkinson's disease. The cause of these symptoms is probably multifactorial but may in part be related to extra-striatal dopamine levels. 6-[(18) F]-Fluoro-L-dopa (FDOPA) positron emission tomography has been widely used to quantify dopamine metabolism in the brain; the most frequently measured kinetic parameter is the tissue uptake rate constant, Ki. However, estimates of dopamine turnover, which also account for the small rate of FDOPA loss from areas of specific trapping, may be more sensitive than Ki for early disease-related changes in dopamine biosynthesis. The purpose of the present study was to compare effective distribution volume ratio (eDVR), a metric for dopamine turnover, to cognitive and behavioral measures in Parkinson's patients. We chose to focus the investigation on anterior cingulate cortex, which shows highest FDOPA uptake within frontal regions and has known roles in executive function. Fifteen non-demented early-stage PD patients were pretreated with carbidopa and tolcapone, a central catechol-O-methyl transferase (COMT) inhibitor, and then underwent extended imaging with FDOPA PET. Anterior cingulate eDVR was compared with composite scores for language, memory, and executive function measured by neuropsychological testing, and behavior change measured using two informant-based questionnaires, the Cambridge Behavioral Inventory and the Behavior Rating Inventory of Executive Function-Adult Version. Lower mean eDVR (thus higher dopamine turnover) in anterior cingulate cortex was related to lower (more impaired) behavior scores. We conclude that subtle changes in anterior cingulate dopamine metabolism may contribute to dysexecutive behaviors in Parkinson's disease.

Topics: Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Benzophenones; Carbidopa; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Dopamine; Female; Gyrus Cinguli; Humans; Male; Middle Aged; Neuropsychological Tests; Nitrophenols; Parkinson Disease; Positron-Emission Tomography; Radiopharmaceuticals; Tolcapone

Catechol-O-methyltransferase inhibitor addition to levodopa/carbidopa formulations improves motor symptoms and reduces levodopa fluctuations in patients with Parkinson's disease. Objectives were to investigate the effects of entacapone and tolcapone on plasma behaviour of levodopa, its metabolite 3-O-methyldopa and on motor impairment. 22 patients orally received levodopa/carbidopa first, then levodopa/carbidopa/entacapone and finally levodopa/carbidopa plus tolcapone within a 4.5 h interval twice. Maximum concentration, time to maximum level and bioavailability of levodopa did not differ between all conditions each with 200 mg levodopa application as a whole. Catechol-O-methyltransferase inhibition caused less fluctuations and higher baseline levels of levodopa after the first intake and less 3-O-methyldopa appearance. The maximum levodopa concentrations were higher after the second levodopa intake, particularly with catechol-O-methyltransferase inhibition. The motor response to levodopa was better with catechol-O-methyltransferase inhibition than without, tolcapone was superior to entacapone. More continuous levodopa brain delivery and lower 3-O-methyldopa bioavailability caused a better motor response during catechol-O-methyltransferase inhibition.

Topics: Aged; Antiparkinson Agents; Area Under Curve; Benzophenones; Carbidopa; Catechol O-Methyltransferase Inhibitors; Catechols; Dose-Response Relationship, Drug; Female; Humans; Levodopa; Male; Middle Aged; Motor Activity; Nitriles; Nitrophenols; Parkinson Disease; Psychomotor Performance; Statistics, Nonparametric; Tolcapone; Treatment Outcome

An increase in neuronal burst activities in the subthalamic nucleus (STN) is a well-documented electrophysiological feature of Parkinson disease (PD). However, the causal relationship between subthalamic bursts and PD symptoms and the ionic mechanisms underlying the bursts remain to be established. Here, we have shown that T-type Ca(2+) channels are necessary for subthalamic burst firing and that pharmacological blockade of T-type Ca(2+) channels reduces motor deficits in a rat model of PD. Ni(2+), mibefradil, NNC 55-0396, and efonidipine, which inhibited T-type Ca(2+) currents in acutely dissociated STN neurons, but not Cd(2+) and nifedipine, which preferentially inhibited L-type or the other non–T-type Ca(2+) currents, effectively diminished burst activity in STN slices. Topical administration of inhibitors of T-type Ca(2+) channels decreased in vivo STN burst activity and dramatically reduced the locomotor deficits in a rat model of PD. Cd(2+) and nifedipine showed no such electrophysiological and behavioral effects. While low-frequency deep brain stimulation (DBS) has been considered ineffective in PD, we found that lengthening the duration of the low-frequency depolarizing pulse effectively improved behavioral measures of locomotion in the rat model of PD, presumably by decreasing the availability of T-type Ca(2+) channels. We therefore conclude that modulation of subthalamic T-type Ca(2+) currents and consequent burst discharges may provide new strategies for the treatment of PD.

Topics: Animals; Benzimidazoles; Cadmium; Calcium; Calcium Channels, T-Type; Cyclopropanes; Dihydropyridines; Disease Models, Animal; Electrophysiology; Male; Mibefradil; Movement; Naphthalenes; Neurons; Nickel; Nitrophenols; Organophosphorus Compounds; Parkinson Disease; Rats; Rats, Wistar

In 1998, the European Medicines Agency suspended the approval for tolcapone in Parkinson's disease (PD) with motor complications due to the drug's implication in fulminant liver failure and the consequent death of 3 patients. Clinical data obtained by ongoing use of tolcapone in other countries proved that adequate safety can be achieved if liver enzymes are strictly monitored. In 2005, tolcapone was relaunched in the European Union under the prerequisite of biweekly liver enzyme monitoring. The objective of this study was to evaluate the compliance with mandatory drug safety monitoring under real-life conditions.. Twenty-one Parkinson's disease patients receiving tolcapone were analyzed with regard to their compliance in performing and reporting the required laboratory tests.. Tolcapone was effective and well tolerated. Yet, less than 25% of the patients regularly performed and reported the required laboratory tests and the compliance declined when comparing the first and second half-years of therapy.. Our data shed light on the incongruity between requirements of postmarketing drug surveillance and every-day reality. The depicted noncompliance is most likely a general problem in postmarketing drug surveillance with an impact for physicians, manufacturers and legal authorities. Practical, legal and ethical aspects will be discussed.

Topics: Adverse Drug Reaction Reporting Systems; Aged; Alanine Transaminase; Antiparkinson Agents; Aspartate Aminotransferases; Benzophenones; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; European Union; Female; Humans; Male; Middle Aged; Nitrophenols; Parkinson Disease; Patient Compliance; Tolcapone

We are reporting our clinical experience in 66 patients with advanced Parkinson's disease (PD) who were switched to tolcapone because of persisting off periods despite treatment with entacapone (according to the European Agency for the Evaluation of Medicinal products: EMEA). We used UPDRS II-III-IV in "on" state to monitor tolcapone effectiveness at 6 and 12 months. We found significant reductions in mean off-time duration (UPDRS item 39) and levodopa dose at follow up. Eleven patients dropped out (17%) during the first month of treatment, 2 (3%) because liver enzymes exceeded normal limit. Amongst patients who continued tolcapone, 30/55 (54%) reported "off-time" reduction > or =25% (UPDRS-39 decrement > or =1 point). Our findings indicate that tolcapone widens the levodopa therapeutic window, even in patients who have not benefited from entacapone. We suggest that tolcapone is indicated before patients are referred for more invasive procedures.

Topics: Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Benzophenones; Female; Follow-Up Studies; Humans; Levodopa; Male; Middle Aged; Nitrophenols; Parkinson Disease; Tolcapone

(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.

Topics: Antiparkinson Agents; Benzophenones; Bromocriptine; Clinical Trials as Topic; Cost-Benefit Analysis; Dopamine Agonists; Hepatitis; Humans; Nitrophenols; Parkinson Disease; Treatment Outcome

The authors report two cases of catechol-O-methyltransferase (COMT) inhibitor-induced asymptomatic hepatic dysfunction in women with Parkinson disease. The patients were genotyped for the UDP-glucuronosyltransferase (UGT) 1A9 gene (which encodes the main COMT inhibitor-metabolizing enzyme), and found to carry mutations leading to defective glucuronidation activity. This suggests that UGT1A9 poor metabolizer genotype(s) may be a predisposing factor for COMT inhibitor-induced hepatotoxicity.

Topics: Adult; Aged; Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Chemical and Drug Induced Liver Injury; DNA Mutational Analysis; Enzyme Inhibitors; Female; Genotype; Glucuronates; Glucuronosyltransferase; Humans; Liver; Liver Diseases; Middle Aged; Mutation; Nitriles; Nitrophenols; Parkinson Disease; Polymorphism, Genetic; Tolcapone; UDP-Glucuronosyltransferase 1A9

Topics: Amantadine; Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Cholinergic Antagonists; Dopamine Agonists; Enzyme Inhibitors; Humans; Levodopa; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

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.

Topics: Age Factors; Age of Onset; Aged; Antiparkinson Agents; Benzophenones; Blood Platelets; Catechols; Dopamine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Nitrophenols; Parkinson Disease; Retrospective Studies; Sex Characteristics; Tolcapone; Tyrosine; Up-Regulation

Inhibition of the catechol-O-methyltransferase (COMT) is an effective treatment for end-of-dose fluctuations in advanced Parkinson's disease. The aim of the present investigation was to analyse the consequences of subsequent alterations in levodopa metabolism under common treatment conditions when the levodopa dose is adjusted due to the occurrence of dyskinesias after initiation of the COMT-inhibitor. Ten patients with advanced Parkinson's disease (Hoehn & Yahr stage IV) were medicated with tolcapone. Prior to and five to ten days after the initiation of tolcapone 300 mg/d, serum level profiles of levodopa and its metabolites (3-O-methyldopa (3-OMD), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)) were performed. The mean daily levodopa dose was reduced from 894 +/- 248 mg to 646 +/- 252 mg (p = 0.003). There was a significant increase in the area under the curve (AUC) of DOPAC during COMT-inhibition compared to the baseline profile (p = 0.009). There were significant decreases of the AUC of HAV (p = 0.001) and the ratios of the AUC HVA / AUC DOPAC (p = 0.0001) and AUC 3-OMD / AUC levodopa (p = 0.0001).. The elevation of DOPAC and the decrease of HVA and HVA / DOPAC reflect a shift of the levodopa metabolism towards the MAO-B dependent oxidative pathway. This might contribute to production of hydroxyl radicals and induction of oxidative stress.

Topics: 3,4-Dihydroxyphenylacetic Acid; Aged; Aged, 80 and over; Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Dihydroxyphenylalanine; Disease Progression; Dose-Response Relationship, Drug; Female; Homovanillic Acid; Humans; Levodopa; Male; Middle Aged; Nitrophenols; Parkinson Disease; Tolcapone; Tyrosine

Entacapone and tolcapone are novel COMT (catechol-O-methyltransferase) inhibitors indicated for the adjunctive treatment of Parkinson's disease (PD) in combination with levodopa. The marketing authorisation of tolcapone was suspended in the European Union (EU) in 1998 mainly due to severe abnormal hepatic reactions. This fact raised concern about the safety of COMT inhibitors in the treatment of parkinsonian patients. In order to investigate whether these COMT inhibitors exhibit different effects on the liver comparative toxicological studies were performed in the rat. Short term toxicological studies in rats at high oral doses of entacapone and tolcapone (200, 400 or 600mg/kg daily) were carried out. Tolcapone (400 mg/kg/day or 600 mg/kg/day) increased mortality after only one week treatment and induced signs of toxicity such as a rise in body temperature, stimulation of respiration and rapid onset of rigor mortis after death. Entacapone did not show any adverse effects at the tested dose levels. In the histopathological examination liver cell necrosis was observed in the tolcapone (400 and 600mg/kg/day) treated rats, but it revealed no treatment related signs of toxicity in entacapone-treated rats. We conclude that the toxicological profile of the two COMT inhibitors, entacapone and tolcapone, differ from each other, tolcapone--unlike entacapone--showed hepatotoxicity.

Topics: Animals; Antiparkinson Agents; Benzophenones; Body Temperature; Catechols; Dose-Response Relationship, Drug; Drug Administration Routes; Enzymes; Liver; Male; Nitriles; Nitrophenols; Parkinson Disease; Rats; Rats, Sprague-Dawley; Survival Rate; Tolcapone

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.

Topics: Aged; Antiparkinson Agents; Benzophenones; Catechols; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Humans; Levodopa; Male; Mental Disorders; Middle Aged; Nitriles; Nitrophenols; Parkinson Disease; Substance Withdrawal Syndrome; Tolcapone

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.

Topics: Aged; Antiparkinson Agents; Benzophenones; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Drug Prescriptions; Female; Humans; Nitrophenols; Parkinson Disease; Product Surveillance, Postmarketing; Tolcapone; United States; United States Food and Drug Administration

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Humans; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

To use pharmacostatistical models to evaluate the overall exposure of patients with Parkinson's disease to levodopa in the presence and absence of tolcapone.. Four hundred twelve patients with Parkinson's disease with fluctuating and nonfluctuating responses to levodopa participated in three multicentered, parallel, double-blind, placebo-controlled dose-finding studies and received either placebo or tolcapone in addition to levodopa-decarboxylase inhibitor therapy. Sparse blood samples were obtained from 393 patients for levodopa and 3-O-methyldopa assay, and the data were analyzed with use of the NONMEM program.. The fraction of levodopa metabolized to 3-O-methyldopa was substantially reduced by the co-administration of tolcapone (by 65%, 74%, and 84% with tolcapone doses of 50, 200, and 400 mg, respectively, in fluctuators, and by 50% and 90% with doses of 200 and 400 mg, respectively, in nonfluctuators). This led to an overall reduction in levodopa clearance (CL) of approximately 15% to 25% in fluctuators and 20% to 30% in nonfluctuators. Because this was partly compensated for by a reduction in levodopa dose in these studies, the total daily exposure of patients to levodopa was only slightly increased (11% to 16%). The peak-trough fluctuations of plasma levodopa (Cmax-Cmin) were reduced in both populations in a dose-dependent fashion.. Tolcapone effectively inhibited the formation of 3-O-methyldopa and resulted in a decrease in levodopa CL. The consequent increase in levodopa bioavailability was mostly offset by reductions in levodopa dose. It is possible that decreased fluctuations in plasma levodopa concentrations rather than increased levodopa exposure may explain the clinical benefits obtained with tolcapone.

Topics: Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Clinical Trials, Phase II as Topic; Double-Blind Method; Enzyme Inhibitors; Female; Half-Life; Humans; Levodopa; Male; Middle Aged; Models, Theoretical; Multicenter Studies as Topic; Nitrophenols; Parkinson Disease; Population Surveillance; Randomized Controlled Trials as Topic; Tolcapone

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Enzyme Inhibitors; Humans; Levodopa; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

Parkinson's disease is a progressive neurodegenerative disorder characterized by striatal dopaminergic loss. Carbidopa/levodopa is the most effective drug treatment for disease management. It reduces bradykinesia and rigidity, but is less effective against tremor. Whether carbidopa/levodopa should be used at the time of initial diagnosis or delayed until symptoms become disabling is controversial. A clinical trial is in progress to help resolve this dilemma. As carbidopa/levodopa loses efficacy with continued use, adjunct therapies using catechol-O-methyl-transferase inhibitors or dopamine agonists may be considered. In younger patients exhibiting parkinsonian symptoms, dopamine agonists may be used as first-line therapy. A new, reversible surgical intervention known as deep-brain stimulator placement is being used to control disabling tremor in patients not responding to optimal drug therapy.

Topics: Age Factors; Aged; Antiparkinson Agents; Benzophenones; Carbidopa; Disease Progression; Drug Administration Schedule; Electric Stimulation Therapy; Humans; Levodopa; Middle Aged; Nitrophenols; Parkinson Disease; Patient Selection; Selegiline; Time Factors; Tolcapone

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Enzyme Inhibitors; Humans; Levodopa; Male; Middle Aged; Nitrophenols; Parkinson Disease; Tolcapone; Vitiligo

In order to study whether the membrane hyperpolarization and firing inhibition caused by dopamine and levodopa on rat midbrain dopamine cells are affected by the inhibition of brain catechol-O-methyl-transferase (COMT), intracellular electrophysiological recordings were made from these neurons maintained in vitro. Here we report that a treatment of the cerebral tissue with tolcapone, a central and peripheral inhibitor of COMT, does not change the membrane responses of midbrain dopamine neurons to dopamine and levodopa. The lack of modification of the dopaminergic effects by tolcapone suggests that the pharmacological inhibition of intracerebral COMT does not have detectable action on dopamine neurotransmission. Therefore, the therapeutic action of tolcapone in Parkinson's disease, might be dependent on the reduction of COMT activity in the extracerebral tissue.

Topics: Animals; Benzophenones; Catechol O-Methyltransferase Inhibitors; Cells, Cultured; Dopamine; Dopamine Antagonists; Electrophysiology; Enzyme Inhibitors; GABA Antagonists; Glycine Agents; Levodopa; Male; Neurons; Nitrophenols; Organophosphorus Compounds; Parkinson Disease; Picrotoxin; Rats; Rats, Wistar; Strychnine; Substantia Nigra; Sulpiride; Synaptic Transmission; Tolcapone; Ventral Tegmental Area

Topics: Amidines; Animals; Antiparkinson Agents; Benzophenones; Brain; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Enzyme Inhibitors; Female; Levodopa; Macaca mulatta; Motor Activity; Nitriles; Nitrophenols; Parkinson Disease; Pregnancy; Pyridones; Rats; Tolcapone

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Drug Approval; Enzyme Inhibitors; Humans; Nitrophenols; Parkinson Disease; Tolcapone; United States; United States Food and Drug Administration

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Enzyme Inhibitors; History, 20th Century; Humans; Nitrophenols; Parkinson Disease; Switzerland; Tolcapone

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Enzyme Inhibitors; Humans; Nitrophenols; Parkinson Disease; Randomized Controlled Trials as Topic; Tolcapone

Two large, randomized, double-blind, placebo-controlled multicenter studies, one North American and one European, examined the efficacy and safety of 300 and 600 mg/day tolcapone in similar populations of patients (n = 379) with Parkinson's disease currently taking levodopa and experiencing motor fluctuations. Change in "on-off" function was the most important end-point assessment. The two studies found similar results. The percentage of "on" time improved significantly and "off" time was reduced. Daily levodopa dosage requirements decreased significantly. The most common and significant adverse event was increased dyskinesia; hallucinations were not frequently encountered.

Topics: Antiparkinson Agents; Benserazide; Benzophenones; Carbidopa; Catechol O-Methyltransferase Inhibitors; Dopamine Agents; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Enzyme Inhibitors; Europe; Humans; Levodopa; Nitrophenols; North America; Parkinson Disease; Randomized Controlled Trials as Topic; Tolcapone

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Dose-Response Relationship, Drug; Drug Costs; Drug Interactions; Enzyme Inhibitors; Humans; Nitrophenols; Parkinson Disease; Tolcapone

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Enzyme Inhibitors; Humans; Levodopa; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

Topics: Aged; Aged, 80 and over; Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Confusion; Drug Administration Schedule; Enzyme Inhibitors; Female; Humans; Male; Nitrophenols; Parkinson Disease; Tolcapone

Topics: Antiparkinson Agents; Benzophenones; Benzothiazoles; Humans; Indoles; Levodopa; Nitrophenols; Parkinson Disease; Pramipexole; Thiazoles; Tolcapone

Topics: Antiparkinson Agents; Benzophenones; Humans; Nitrophenols; Parkinson Disease; Tolcapone

Topics: Aged; Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Confusion; Drug Interactions; Dyskinesia, Drug-Induced; Enzyme Inhibitors; Humans; Levodopa; Nitrophenols; Parkinson Disease; Tolcapone

Topics: Aged; Antiparkinson Agents; Benzophenones; Chemical and Drug Induced Liver Injury; Female; Humans; Liver Failure, Acute; Nitrophenols; Parkinson Disease; Tolcapone

Topics: Antiparkinson Agents; Benzophenones; Brain; Humans; Nitrophenols; Parkinson Disease; Tolcapone

The uptake rate constant and the loss rate constant that expresses the reversibility of the uptake process of 6-[18F]fluoro-L-Dopa (FDOPA) were measured by positron emission tomography in the striatum of normal rhesus monkeys and in monkeys with unilateral lesions of the dopaminergic nigro-striatal pathway, induced by intracarotid injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Each animal was studied twice: with and without pretreatment of the catechol-O-methyltransferase (COMT) inhibitor Ro 40-7592, tolcapone. After pretreatment with tolcapone, there was a very significant increase in plasma FDOPA throughout the course of the study, accompanied by a significant decrease in its main metabolite, 3-O-methylfluorodopa. Tolcapone did not induce a significant change in the uptake rate constant in either the normal or the MPTP-treated striatum. However, after tolcapone pretreatment, there was a significant decrease in the loss rate constant in the MPTP-treated striatum (25%) and a smaller, non-significant decrease in the normal striatum (13%). It is concluded that the COMT inhibitor tolcapone exhibits clear peripheral and central activity. As compared to peripheral COMT inhibitors, this central effect may help preserve and stabilize the synaptic levels of DA and, thus, further improve the effects of L-DOPA therapy in parkinsonian patients.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Benzophenones; Catechol O-Methyltransferase; Disease Models, Animal; Enzyme Inhibitors; Levodopa; Macaca mulatta; Nitrophenols; Parkinson Disease; Tolcapone

Topics: Aged; Antiparkinson Agents; Benzophenones; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Nitrophenols; Parkinson Disease; Tolcapone

Topics: Antiparkinson Agents; Benzophenones; Humans; Levodopa; Monoamine Oxidase Inhibitors; Nitrophenols; Parkinson Disease; Tolcapone

Topics: Antiparkinson Agents; Benzophenones; Catechol O-Methyltransferase Inhibitors; Drug Synergism; Enzyme Inhibitors; Humans; Levodopa; Nitrophenols; Parkinson Disease; Tolcapone

We compared the concentrations of dopaminergic substances in the plasma and cerebrospinal fluid (CSF) with clinical severity in patients with Parkinson's disease (PD) under L-dopa/carbidopa treatment and under L-dopa/carbidopa+tolcapone treatment. Compared with treatment with L-dopa/carbidopa alone, the co-administration of tolcapone produced a significant decrease in clinical severity; a remarkable reduction in the 3-O-methyldopa (3-OMD) concentration and significant increase in the L-dopa concentration both in the plasma and CSF; and a significant increase in the dopamine concentration in the CSF. The clinical effects of tolcapone were closely correlated with the reduction in the 3-OMD concentration, but not with the increase in the dopamine and L-dopa concentrations in the CSF.

Topics: 3,4-Dihydroxyphenylacetic Acid; Aged; Antiparkinson Agents; Benzophenones; Carbidopa; Catechol O-Methyltransferase Inhibitors; Dopamine; Homovanillic Acid; Humans; Levodopa; Middle Aged; Nitrophenols; Parkinson Disease; Tolcapone; Tyrosine

Positron emission tomography (PET) following intravenous administration of beta-[11C]-L-DOPA provides a method of assessing regional cerebral uptake and utilization of levodopa. Cerebral levodopa kinetics in the rhesus monkey were investigated after the inhibition of catechol-O-methyltransferase (COMT) with RO 40-7592, and after coadministration of the peripheral aromatic L-amino acid decarboxylase (AADC) inhibitors benserazide and carbidopa. Pretreatment with RO 40-7592 (10 mg/kg), benserazide (10 mg/kg) or carbidopa (3.5 mg/kg) did not change striatal k3, which mainly reflects the ability for the brain tissue to convert [11C]-L-DOPA to [11 C]-dopamine, although the brain's uptake of radioactivity increased substantially after pretreatment with the AADC inhibitors. When benserazide was coadministered with RO 40-7592 (10 mg/kg) a dose-dependent decrease in striatal k3 was measured with an apparent ED50 of 3 mg/kg. No such effect was indicated after pretreatment with the combination of RO 40-7592 (10 mg/kg) and carbidopa (3.5 mg/kg). The possible negative interactions of coadministration with COMT inhibitors and predominantly peripherally acting AADC inhibitors must be considered when used in the therapy of Parkinson's disease.

Topics: Animals; Benserazide; Benzophenones; Brain; Catechol O-Methyltransferase Inhibitors; Levodopa; Macaca mulatta; Nitrophenols; Parkinson Disease; Tolcapone; Tomography, Emission-Computed

Behavioural and some neurochemical effects of Ro 40-7592 (3,4-dihydroxy-4'-methyl-5-nitrobenzophenone), a new COMT inhibitor, were studied in rats and mice. Ro 40-7592 increased the effect of L-DOPA (plus benserazide) on locomotor activity, reserpine-induced hypothermia, and catalepsy induced by pimozide, haloperidol and fluphenazine. Locomotor hyperactivity induced by amphetamine or nomifensine, as well as stereotypy induced by amphetamine (but not apomorphine), were also increased by Ro 40-7592. The drug stimulated exploratory activity in the open field test. It decreased the levels of HVA and 3-MT, increased the level of DOPAC but did not change the levels of dopamine in the striatum, nucleus accumbens and frontal cortex. These results indicate that Ro 40-7592 may improve the therapy with L-DOPA (plus decarboxylase inhibitor) of Parkinson's disease.

Topics: Animals; Antipsychotic Agents; Benzophenones; Catalepsy; Catechol O-Methyltransferase; Dopamine; Dose-Response Relationship, Drug; Enzyme Inhibitors; Levodopa; Male; Mice; Motor Activity; Nitrophenols; Nomifensine; Parkinson Disease; Rats; Rats, Inbred Strains; Stereotyped Behavior; Tolcapone