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PubMed2005

Two patients with COMT inhibitor-induced hepatic dysfunction and UGT1A9 genetic polymorphism.

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.

Adult↗
PubMed1992

Catechol-O-methyltransferase inhibition increases striatal L-dopa and dopamine: an in vivo study in rats.

We administered Ro 40-7592, an inhibitor of the enzyme catechol-O-methyltransferase (COMT) that crosses the blood-brain barrier, to rats and monitored extracellular catecholamine levels in the corpus striatum before and after the intraperitoneal administration of a bolus of l-dopa. Acute administration of Ro 40-7592 increased basal levels of l-dopa and dihydroxyphenylacetic acid (DOPAC) and decreased basal homovanillic acid (HVA) levels, but did not affect basal dopamine levels. In rats treated with Ro 40-7592, l-dopa administration produced a greater increase in striatal levels of l-dopa, dopamine, and DOPAC than it did in controls, while HVA formation was attenuated. We conclude that inhibition of COMT activity promotes central dopamine synthesis and release following administration of pharmacologic doses of l-dopa.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2004

Safety and tolerability of COMT inhibitors.

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.

Aged↗
PubMed2001

[Pharmacological treatments of Parkinson's disease].

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.

Amantadine↗
PubMed2000

New drugs for the treatment of Parkinson's disease.

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.

Antiparkinson Agents↗
PubMed1999

Medical treatment of later-stage motor problems of Parkinson disease.

Parkinson disease progression is associated with the development of levodopa short-duration responses and dyskinesias, as well as gait freezing. Levodopa dose adjustment and adjunctive treatment with dopamine agonists form the major therapeutic strategies. Catechol O-methyltransferase inhibitors are also appropriate considerations, whereas other drugs, including selegiline, amantadine, anticholinergic agents, and propranolol, have a more minor role.

Amantadine↗
PubMedDate not supplied

[Entacapone++ : a new catechol-O-methyltransferase inhibitor which improves the response to levodopa in patients with Parkinson disease and fluctuating motor function].

INTRODUCTION AND DEVELOPMENT: Selective inhibitors of peripheral catechol-O-methyltransferase (COMT) seem to be useful drugs for the treatment of patients with Parkinson's disease. When associated with levadopa and a dopa-decarboxylase inhibitor they are clearly effective in patients with progressive illness, who are particularly dependent on the plasma concentration of levadopa, or may have fluctuating motor function when the effect of the dose is wearing off. Entacapone, a prototype of this group of drugs, has been shown to modify the pharmacokinetics of levadopa in such a way that the plasma concentration of levadopa is raised (between 21% and 50% in different studies): to reduce variations in plasma level between doses, which allows some patients to reduce the total daily dose of levadopa at the same time as the response time (time 'on') increases by between 20% and 78%. CONCLUSION: Entacapone is a well tolerated drug and could form part of a regular 'triple therapy' in the patients described.

Antiparkinson Agents↗
PubMed1999

[COMT inhibitors].

Explore the source record for details and available documents.

Antiparkinson Agents↗
PubMed1999

What is new in movement disorders?

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.

Antiparkinson Agents↗
PubMed1999

Parkinson's disease: therapeutic choices and timing decisions in patient management. Interview by Wayne Kuznar.

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.

Age Factors↗
PubMed2000

[A prospect of treatment for Parkinson's disease in the 21st century].

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.

Animals↗
PubMedDate not supplied

[The usefulness of dopaminergic drugs in traumatic brain injury].

OBJECTIVE: To review the bibliography indexed in MEDLINE so as to assess and/or compare the usefulness and indications of dopaminergic drugs in both cognitive and motor disorders due to head injuries (traumatic brain injury). DEVELOPMENT: Lesions due to head injuries cause both focal and diffuse cerebral damage which lead to neuropsychological and motor deficit. It is clear that motor alterations cause major physical disability, but neuropsychological alterations affect cognitive behaviour and emotional aspects which are very disabling and seriously affect both the patient and his family and also his return to social, family and working life. There is a wide range of drugs available to assist in the improvement or recovery of the patient. Some of the most important of these drugs are the dopaminergic agents, due to the importance of dopamine for proper frontal cerebral area function. CONCLUSIONS: This study confirms the indications for the use of dopaminergeric drugs when trying to improve or accelerate recovery from cognitive deficits in patients with traumatic cerebral damage. However, it is important to note that, in view of the complexity of cognitive function and the mechanisms of their recovery, it will be necessary to make randomized, double blind, prospective studies with a control group (if possible) so as to determine the real part played by these drugs in the recovery process of patients with traumatic brain damage.

Amantadine↗
PubMed2004

[A comparative study of efficacy of dopamine receptors agonists and catechol-O-methyltransferase in the treatment of late stages of Parkinson's disease].

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.

Activities of Daily Living↗