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Parkinsn Current Topics
TITLE: Clinical pharmacology, therapeutic use and
potential of COMT inhibitors in Parkinson's disease [In Process
Citation]
AUTHORS: Kaakkola S
AUTHOR AFFILIATION: Department of Neurology, University of
Helsinki, Finland.
SOURCE: Drugs 2000 Jun;59(6):1233-50
[MEDLINE record in process]
CITATION IDS: PMID: 10882160 UI: 20338008
ABSTRACT: When peripheral decarboxylation is blocked by carbidopa
or benserazide, the main metabolic pathway of levodopa is
O-methylation by catechol-O-methyltransferase (COMT). Entacapone
and tolcapone are new potent, selective and reversible
nitrocatechol-type COMT inhibitors. Animal studies have
demonstrated that entacapone mainly has a peripheral effect
whereas tolcapone also inhibits O-methylation in the brain. In
human volunteers, both entacapone and tolcapone dose-dependently
inhibit the COMT activity in erythrocytes, improve the
bioavailability and decrease the elimination of levodopa, and
inhibit the formation of 3-O-methyldopa (3-OMD). Entacapone is
administered with every scheduled dose of levodopa whereas
tolcapone is administered 3 times daily. The different
administration regimens for these agents are based on their
different pharmacokinetic and pharmacodynamic profiles. Both
entacapone and tolcapone enhance and extend the therapeutic
effect of levodopa in patients with advanced and fluctuating
Parkinson's disease. They prolong the duration of levodopa
effect. Clinical studies show that they increase the daily ON
time by an average 1 to 3 hours, improve the activities of daily
living and allow daily levodopa dosage to be decreased.
Correspondingly, they significantly reduce the daily OFF time. No
comparative studies between entacapone and tolcapone have been
performed. Tolcapone also appears to have a beneficial effect in
patients with nonfluctuating Parkinson's disease. The main
adverse effects of the COMT inhibitors are related to their
dopaminergic and gastrointestinal effects. Enhancement of
dopaminergic activity may cause an initial worsening of
levodopa-induced adverse effects, such as dyskinesia, nausea,
vomiting, orthostatic hypotension, sleep disorders and
hallucinations. Levodopa dose adjustment is recommended to avoid
these events. Tolcapone is associated with diarrhoea in about 16
to 18% of patients and entacapone in less than 10% of patients.
Diarrhoea has led to discontinuation in 5 to 6% of patients
treated with tolcapone and in 2.5% of those treated with
entacapone. Urine discoloration to dark yellow or orange is
related to the colour of COMT inhibitors and their metabolites.
Elevated liver transaminase levels are reported in 1 to 3% of
patients treated with tolcapone but very rarely, if at all, in
patients treated with entacapone. The descriptions of acute,
fatal fulminant hepatitis and potentially fatal neurological
reactions, such as neuroleptic malignant syndrome and
rhabdomyolysis, in association with tolcapone led to the
suspension of its marketing authorisation in the European
Community and Canada. In many other countries, the use of
tolcapone is restricted to patients who are not responding
satisfactorily to other therapies. Regular monitoring of liver
enzymes is required if tolcapone is used. No such adverse
reactions have so far been described for entacapone and no
laboratory monitoring has been proposed. COMT inhibitors added to
levodopa therapy are beneficial, particularly in patients with
fluctuating disease. They may be combined with other
antiparkinsonian drugs, such as dopamine agonists, selegiline and
anticholinergics without adverse interactions. They provide a new
treatment possibility in patients with Parkinson's disease who
have problems with their present levodopa therapy.
2000/07
2000/06 11:00
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TITLE: Population pharmacokinetics of levodopa in
patients with Parkinson's disease treated with tolcapone.
AUTHORS: Jorga K; Banken L; Fotteler B; Snell P; Steimer JL
AUTHOR AFFILIATION: Department of Research and Development, F.
Hoffmann-La Roche Ltd, Basel, Switzerland. karin.jorga@roche.com
SOURCE: Clin Pharmacol Ther 2000 Jun;67(6):610-20
CITATION IDS: PMID: 10872643 UI: 20329044
ABSTRACT: OBJECTIVE: To use pharmacostatistical models to
evaluate the overall exposure of patients with Parkinson's
disease to levodopa in the presence and absence of tolcapone.
METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
2000/07
2000/08 11:00
--------------------------------------------------------------------------------
TITLE: The role of entacapone in the management of
Parkinson's disease.
AUTHORS: Brooks DJ; Forsyth D; Playfer JR; Williams AC
AUTHOR AFFILIATION: Imperial College School of Medicine,
Hammersmith Hospital, London.
SOURCE: Hosp Med 2000 Apr;61(4):267-71
CITATION IDS: PMID: 10858804 UI: 20316608
ABSTRACT: Catechol-O-methyltransferase (COMT) inhibition is an
important advance in the treatment of Parkinson's disease. This
consensus statement provides guidelines for the optimal use of
the only currently available COMT inhibitor, entacapone (Comtess,
Orion Pharma (UK) Ltd, Newbury, Berkshire).
2000/07
2000/15 11:00
--------------------------------------------------------------------------------
TITLE: Catechol-O-methyltransferase (COMT) inhibitors in
Parkinson's disease.
AUTHORS: Waters C
AUTHOR AFFILIATION: Columbia University, Department of Neurology,
New York, New York 10032, USA.
SOURCE: J Am Geriatr Soc 2000 Jun;48(6):692-8
CITATION IDS: PMID: 10855610 UI: 20312300
ABSTRACT: 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.
2000/07
2000/06 11:00
--------------------------------------------------------------------------------
TITLE: Clinical, pharmacokinetic, and pharmacodynamic
effects of tolcapone withdrawal in levodopa-treated patients with
parkinsonism.
AUTHORS: Jorga KM; Davis TL; Kurth MC; Saint-Hilaire MH; LeWitt
PA; Fotteler B; Zurcher G; Rabbia M
AUTHOR AFFILIATION: Department of Research and Development, F.
Hoffmann-La Roche, Basel, Switzerland.
SOURCE: Clin Neuropharmacol 2000 Mar-Apr;23(2):98-105
CITATION IDS: PMID: 10803800 UI: 20260945
ABSTRACT: The effect and clinical significance of tolcapone
withdrawal on erythrocyte catechol-O-methyltransferase (COMT)
activity, levodopa pharmacokinetics, and levodopa requirements
were investigated in 59 patients with fluctuating parkinsonism
who were randomized to receive placebo or tolcapone 100 or 200 mg
three times daily for 6 weeks. Tolcapone withdrawal caused a
transient elevation in COMT activity by 64% in patients receiving
100 mg three times daily and by 128% in those receiving 200 mg
three times daily at approximately 1-2 weeks after
discontinuation of drug. Thereafter, COMT activity was declining
but did not reach baseline values by the 12-week study endpoint.
However, this had no effect on plasma levodopa and 3-O-methyldopa
(3-OMD) concentrations or on levodopa requirements. During
treatment, tolcapone increased "on" time and decreased
"off" time; after discontinuation of study medication
and levodopa dose adjustment, on and off times were similar to
baseline. Withdrawal was generally well tolerated; no patients
withdrew from the trial during the posttreatment period, and no
serious adverse events were observed. In conclusion, the
transient increase in erythrocyte COMT activity observed after
discontinuation oftolcapone is not associated with changes in
peripheral levodopa metabolism and therefore has no significant
clinical consequences in terms of levodopa requirements, clinical
symptoms, or adverse events.
2000/07
2000/15 11:00
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