| Neurologia. 2005
May;20(4):180-8.
[Optimization of use of levodopa in Parkinson's disease: role
of levodopa-carbidopa-entacapone combination.]
[Article in Spanish]
Castro A, Valldeoriola F, Linazasoro G, Rodriguez-Oroz M, Stochi F, Marin
C, Rodriguez M, Vaamonde J, Jenner P, Alvarez L, Pavon N, Macias R, Luquin
M, Hernandez B, Grandas F, Gimenez-Roldan S, Tolosa E, Obeso J.
Servicio de Neurologia. Hospital Xeral de Galicia. Santiago de Compostela.
Levodopa remains the mainstay treatment for Parkinson's disease (PD).
Chronic treatment is associated with motor complications (MC) that marred
the clinical benefit of levodopa. These problems and experimental data
in cell cultures indicating a neurotoxic effect of levodopa have led to
the idea of delaying the introduction of levodopa treatment for as long
as possible. We here review recent data regarding the mechanism of action
of levodopa and its application in clinical practice on the light of the
marketing of the combination levodopa-carbidopa- entacapone. Accumulated
evidence indicates that MC are mainly the consequence of disease severity
governing the degree of dopaminergic depletion and the <<pulsatile>>
dopaminergic stimulation provided by levodopa short plasma half-life.
There is no in vivo or clinical evidence of a relevant neurotoxic effect
of levodopa. In fact, the recent ELLDOPA study may suggest a neuroprotective
effect. Entacapone reduces homocysteine plasma levels which could provide
a mechanism to reduce cell death in PD. Currently, the combination levodopa-carbidopa-entacapone
is particularly indicated for the treatment of <<wearing off>>
fluctuations. Experimental evidence suggests that early treatment with
levodopa-carbidopa-entacapone may substantially ameliorate the incidence
of MC. Such a clinical study in <<de novo>> patients is underway.
At present, the combination levodopa-carbidopaentacapone is indicated
when levodopa is judged necessary. Neurologia 2005;20(4):180-188.
Prescrire Int. 2005 Apr;14(76):51-4.
Levodopa + carbidopa + entacapone. Entacapone: a second look:
new preparations. Parkinson's disease: a modest effect.
[No authors listed]
(1) If patients with Parkinson's disease treated with levodopa develop
end-of-dose motor fluctuations, the standard therapy is to add bromocriptine,
a dopamine receptor agonist, to their ongoing treatment. (2) Evaluation
data available in 1999 on entacapone, a catechol-o-methyltransferase (COMT)
inhibitor, failed to show whether the balance of benefits versus harm
was at least equivalent to that of bromocriptine. (3) Entacapone is now
also available as a triple fixed-dose combination with levodopa + carbidopa.
(4) Three double-blind trials have compared triple combinations of levodopa
+ carbidopa (or benserazide) + entacapone with levodopa + carbidopa (or
benserazide) + placebo. Two of these trials showed an increase of about
1 hour in "on" phases during the day, together with a small
reduction in the daily dose of levodopa. These results are consistent
with earlier studies. (5) Entacapone has still not been compared with
a dopamine agonist. (6) The fixed-dose combination of levodopa + carbidopa
+ entacapone has been compared with unfixed combinations in two unblinded
trials only. (7) These two trials showed that efficacy was similar whether
entacapone was used separately or included in a fixed-dose combination
with levodopa + carbidopa. The only relevant trial (a non randomised cross-over
trial) failed to show patient preference for the fixed-dose combination.
(8) In France, a short-acting combination of levodopa and carbidopa is
available, with a dose ratio of 10:1. This compares to a ratio of 4:1
for levodopa and carbidopa in the fixed-dose combination of levodopa +
carbidopa + entacapone. The dose of carbidopa is therefore higher for
a given dose of levodopa, provoking more dyskinesias and nausea. (9) Entacapone
can cause drowsiness. Cases of cholestatic hepatitis have also been reported.
Risks of liver toxicity, rhabdomyolysis and neuroleptic malignant syndrome
remain to be determined. (10) In practice, bromocriptine remains the first-choice
for adjunctive therapy when levodopa becomes ineffective.
Int J Clin Pract. 2005 Mar;59(3):287-90.
Efficacy of levodopa and carbidopa on visual function in patients
with non-arteritic anterior ischaemic optic neuropathy.
Simsek T, Eryilmaz T, Acaroglu G.
Department of Ophthalmology, Ankara University Medical School, Ankara,
Turkey.
The benefit of levodopa and carbidopa therapy in improving visual function
in patients with non-arteritic anterior ischaemic neuropathy (NAION) was
evaluated. Twenty-four subjects with NAION were randomly selected to receive
either levodopa-carbidopa or a placebo. Visual functions of neither the
study nor the placebo groups showed improvement. Side effects of levodopa
such as dizziness, orthostatic hypotension, vomiting and cardiac arrhythmia
were seen. Levodopa and carbidopa had no therapeutic effect on visual
recovery in our patients with NAION.
Mov Disord. 2005 Feb 22; [Epub ahead of print] Related Articles, Links
Long-term efficacy and safety of pramipexole in advanced Parkinson's
disease: Results from a European Multicenter Trial.
Moller JC, Oertel WH, Koster J, Pezzoli G, Provinciali L.
Department of Neurology, Philipps-University Marburg, Germany.
A double-blind, placebo-controlled study with a subsequent open-label
phase was conducted in 354 patients with Parkinson's disease (PD) and
motor fluctuations under individually adjusted therapy with levodopa.
During the double-blind phase 174 patients received pramipexole and 180
placebo. In agreement with previous studies, pramipexole treatment improved
UPDRS sum scores of parts II and III by 30% and off times by approximately
2.5 hours per day. Differences between the treatment groups became significant
at a daily dose of 0.75 mg of pramipexole dihydrochloride. We, furthermore,
performed post hoc analyses with respect to resting tremor and depression.
Patients with pronounced resting tremor derived a clear benefit from pramipexole
treatment compared with placebo. In addition, pramipexole significantly
improved the subitems motivation/initiative and depression in a subpopulation
with increased Unified Parkinson's Disease Rating Scale I scores at the
time of inclusion. There were 262 patients who were subsequently enrolled
into the open-label study featuring a maximum duration of up to 57 months.
Statistical analysis revealed good long-term efficacy and tolerability
of pramipexole. Overall, only a low prevalence of somnolence was found.
In summary, this study provides additional level I evidence of the usefulness
of pramipexole, suggests a particular tremorlytic and a possible antidepressant
action of this compound, and addresses for the first time its efficacy
and safety during long-term administration in advanced PD. (c) 2005 Movement
Disorder Society.
J Psychiatr Res. 2005 May;39(3):241-250. Related Articles, Links
Psychometric schizotypy modulates levodopa effects on lateralized
lexical decision performance.
Mohr C, Krummenacher P, Landis T, Sandor PS, Fathi M, Brugger
P.
Department of Neurology, Functional Brain Mapping Laboratory, University
Hospital Geneva, Rue Micheli-du-Crest 24, 1211 Geneva 14, Switzerland;
Rehabilitation Clinic, University Hospital Geneva, Geneva, Switzerland;
Department of Neurology, University Hospital Zurich, Zurich, Switzerland.
Emergence of psychotic thought has been related to a breakdown in left-hemisphere
language dominance. Dopamine (DA) is implicated in both psychotic pathology
and modulation of the semantic system. The present study explored whether
controlled DA administration modulates basic language functions: (1) in
general and/or (2) as a function of schizophrenia-associated thought.
Forty healthy men performed a tachistoscopic lexical decision task. Participants'
performance was also analyzed as a function of their positive (magical
ideation, MI) and negative (physical anhedonia, PHYSAN) schizotypal features.
Half of the subjects received 200 mg levodopa, the other half a placebo.
Our findings showed that pharmacological treatment per se did not influence
task performance, but influenced laterality patterns as a function of
participants' schizotypal features. In the placebo, but not in the levodopa
group, right hemisphere language contribution increased as a function
of increasing MI scores. In the levodopa, but not in the placebo group,
superior left hemisphere lexical decision performance was related to increasing
PHYSAN scores. The findings from both substance groups suggest that in
the healthy brain, a DA agonist restores left-hemispheric dominance for
language by reducing right-hemispheric contribution with respect to a
positive schizotypal trait and by increasing left-hemispheric specialization
with respect to a negative schizotypal trait. We conjecture that the healthy
brain compensates through intact neurochemical mechanisms an increased
DA concentration, in particular for persons with elevated positive psychotic-like
features.
J Chromatogr B Analyt Technol Biomed Life Sci. 2004 Nov 5;811(1):93-101
3-Methoxytyramine as an indicator of dopaminergic manipulation in the
equine athlete.
Wynne PM, Vine JH, Amiet RG.
Racing Analytical Services Limited, 400 Epsom Road, Flemington, Vic. 3031,
Australia.
The influence of sampling variables on the concentration of the dopamine
metabolites 3-methoxytyramine (3MT), dihydroxyphenylacetic acid (DOPAC)
and homovanilic acid (HVA) was examined in equine urine. A logarithmic
transformation of the data for all horses gave distribution which approximated
the normal distributions for each metabolite. The mean urinary concentration
of 3MT in horses was 214ng/mL and the application of a threshold with
a probability of 1 in 10,000 gave an actionable level of 4microg/mL. Environmental
variables were not forensically significant in determining the population
distribution. HVA was not found to be a reliable indicator of dopamine
or levodopa administration.
Brain. 2004 Nov;127(Pt 11):2441-51. Epub 2004 Sep 30.
Frontotemporal lobar degeneration with ubiquitin-only-immunoreactive
neuronal changes: broadening the clinical picture to include progressive
supranuclear palsy.
Paviour DC, Lees AJ, Josephs KA, Ozawa T, Ganguly M, Strand C, Godbolt
A, Howard RS, Revesz T, Holton JL.
The Sara Koe PSP Research Centre, Institute of Neurology, London, UK.
The frontotemporal lobar degenerations (FTLDs) are a group of disorders
in which the clinical picture is not necessarily predictive of the underlying
neuropathology. The FTLD with ubiquitin-only-immunoreactive neuronal changes
(FTLD-U) subtype is pathologically characterized by ubiquitin-positive,
tau and alpha-synuclein-negative neuronal cytoplasmic inclusions in the
frontotemporal cortex and hippocampal dentate fascia. When similar pathological
changes are accompanied by histological features of motor neuron disease
(MND), the term FTLD-MND is used. The latter pathological changes may
be found in patients with or without clinical evidence of MND. We retrospectively
reviewed the clinical details of three patients with a rapidly progressive,
levodopa-unresponsive bradykinetic-rigid syndrome and frontal cognitive
impairment. A diagnosis of progressive supranuclear palsy (PSP) had been
considered in all three cases at initial presentation. Two of the cases
fulfilled clinical diagnostic criteria for PSP, which was the final clinical
diagnosis during life. Pathological analysis showed typical histological
appearances of FTLD-MND in two cases and of FTLD-U in one case. Semi-quantitative
analysis of pathological load seemed to correlate with the clinical phenotype.
FTLD-U or FTLD-MND should be considered in the differential diagnosis
of progressive frontal dementia with an akinetic rigid syndrome and supranuclear
gaze palsy or Steele-Richardson-Olszewski disease.
J Neurol Neurosurg Psychiatry. 2004 Nov;75(11):1617-9.
Pathophysiology of parkinsonism due to hydrocephalus.
Racette BA, Esper GJ, Antenor J, Black KJ, Burkey A, Moerlein SM, Videen
TO, Kotagal V, Ojemann JG, Perlmutter JS.
Washington University School of Medicine, 660 South Euclid Ave, Box 8111,
St. Louis, MO 63110. racetteb@neuro.wustl.edu.
We report a patient with hydrocephalus who developed levodopa responsive
parkinsonism and severe bradyphrenia associated with shunt malfunction
and revision. Magnetic resonance imaging revealed periaqueductal edema
involving medial substantia nigra. [(18)F]dopa positron emission tomography
demonstrated reduced uptake in the caudate and putamen with relative sparing
of the posterior putamen. Hydrocephalus associated with shunt malfunction
can cause a distinct parkinsonian syndrome with greater dysfunction of
projections from the medial substantia nigra to anterior striatum than
in idiopathic Parkinson's disease.
Neurobiol Dis. 2004 Nov;17(2):219-36.
Transcriptome analysis in a rat model of l-DOPA-induced dyskinesia.
Konradi C, Westin JE, Carta M, Eaton ME, Kuter K, Dekundy A, Lundblad
M, Cenci MA.
Laboratory of Neuroplasticity, McLean Hospital, Belmont, MA 02478, USA;
Department of Psychiatry, Harvard Medical School, Boston, MA 02115, USA.
We have examined the pattern of striatal messenger RNA expression of over
8000 genes in a rat model of levodopa (l-DOPA)-induced dyskinesia and
Parkinson disease (PD). 6-Hydroxydopamine (6-OHDA)-lesioned rats were
treated with l-DOPA or physiological saline for 22 days and repeatedly
tested for antiakinetic response to l-DOPA and the development of abnormal
involuntary movements (AIMs). In a comparison of rats that developed a
dyskinetic motor response to rats that did not, we found striking differences
in gene expression patterns. In rats that developed dyskinesia, GABA neurons
had an increased transcriptional activity, and genes involved in Ca(2+)
homeostasis, in Ca(2+)-dependent signaling, and in structural and synaptic
plasticity were upregulated. The gene expression patterns implied that
the dyskinetic striatum had increased transcriptional, as well as synaptic
activity, and decreased capacity for energy production. Some basic maintenance
chores such as ribosome protein biosynthesis were downregulated, possibly
a response to expended ATP levels.
Neurology. 2004 Oct 12;63(7):1245-50.
Cannabis for dyskinesia in Parkinson disease: a randomized double-blind
crossover study.
Carroll CB, Bain PG, Teare L, Liu X, Joint C, Wroath C, Parkin SG, Fox
P, Wright D, Hobart J, Zajicek JP.
Department of Neurology, Derriford Hospital, Plymouth, UK. cbc@doctors.org.uk
BACKGROUND: The long-term treatment of Parkinson disease (PD) may be complicated
by the development of levodopa-induced dyskinesia. Clinical and animal
model data support the view that modulation of cannabinoid function may
exert an antidyskinetic effect. The authors conducted a randomized, double-blind,
placebo-controlled crossover trial to examine the hypothesis that cannabis
may have a beneficial effect on dyskinesia in PD. METHODS: A 4-week dose
escalation study was performed to assess the safety and tolerability of
cannabis in six PD patients with levodopa-induced dyskinesia. Then a randomized
placebo-controlled crossover study (RCT) was performed, in which 19 PD
patients were randomized to receive oral cannabis extract followed by
placebo or vice versa. Each treatment phase lasted for 4 weeks with an
intervening 2-week washout phase. The primary outcome measure was a change
in Unified Parkinson's Disease Rating Scale (UPDRS) (items 32 to 34) dyskinesia
score. Secondary outcome measures included the Rush scale, Bain scale,
tablet arm drawing task, and total UPDRS score following a levodopa challenge,
as well as patient-completed measures of a dyskinesia activities of daily
living (ADL) scale, the PDQ-39, on-off diaries, and a range of category
rating scales. RESULTS: Seventeen patients completed the RCT. Cannabis
was well tolerated, and had no pro- or antiparkinsonian action. There
was no evidence for a treatment effect on levodopa-induced dyskinesia
as assessed by the UPDRS, or any of the secondary outcome measures. CONCLUSIONS:
Orally administered cannabis extract resulted in no objective or subjective
improvement in dyskinesias or parkinsonism.
Acta Neurol Scand. 2004 Oct;110(4):260-6.
The effect of monoamine oxidase B (MAOB) and catechol-O-methyltransferase
(COMT) polymorphisms on levodopa therapy in patients with sporadic Parkinson's
disease.
Bialecka M, Drozdzik M, Klodowska-Duda G, Honczarenko K, Gawronska-Szklarz
B, Opala G, Stankiewicz J.
Department of Experimental and Clinical Pharmacology, Pomeranian Medical
University, Szczecin.
OBJECTIVES: The etiology of sporadic idiopathic Parkinson's disease (PD)
is considered multifactorial with both genetic and environmental factors
modifying the disease expression. Recent studies suggest that polymorphism
in monoamine oxidase B (MAOB) and catechol-O-methyltransferase (COMT)
might influence the risk and treatment of PD. The aim of the study was
to evaluate the effect of MAOB and COMT genetic polymorphism on effective
daily dose of levodopa applied during the first 5 years of treatment,
and to find out if a relationship exists between MAOB and COMT haplotypes
and motor disturbances onset in PD patients treated with levodopa preparations.
MATERIALS AND METHODS: A total of 95 patients (40 females and 55 males)
of Polish origin diagnosed with sporadic PD were enrolled into the study,
and were divided into two groups. Group 1 - patients treated with doses
of levodopa below 500 mg/day during the first 5 years of treatment. Group
2 - patients requiring levodopa doses exceeding 500 mg/24 h during the
first 5 years of treatment. Low activity alleles of MAOB and COMT, i.e.
MAOB allele A and COMT(L) as well as high activity ones, i.e. MAOB allele
G and COMT(H), were determined using PCR-RFLP method. RESULTS: No statistically
significant differences were found in MAOB and COMT allele distribution
in the two groups. However, the frequency of COMT(L/L) homozygotes was
higher in the group treated with low doses of levodopa when compared with
the second group. MAOB and COMT AG-HH haplotype predominated in the group
of females treated with high daily doses of levodopa when compared with
AG-LL haplotype in the group of females treated with low daily doses of
levodopa (<500 mg/24 h). CONCLUSION: The results of the study suggest
that patients with COMT(L/L) genotype and possibly MAOB genotype A may
benefit from more efficient and safer levodopa therapy.
Arch Neurol. 2004 Oct;61(10):1563-8.
Double-blind, Placebo-Controlled Study of Entacapone in Levodopa-Treated
Patients With Stable Parkinson Disease.
Olanow CW, Kieburtz K, Stern M, Watts R, Langston JW, Guarnieri M, Hubble
J.
Author Affiliations: Department of Neurology, Mount Sinai School of Medicine,
New York, NY.
BACKGROUND: The catechol O-methyltransferase inhibitor entacapone acts
by extending the elimination half-life of levodopa and is currently approved
as an adjunct to levodopa for the treatment of patients with Parkinson
disease (PD) with motor fluctuations. OBJECTIVE: To determine if the addition
of entacapone administration provides benefit to levodopa-treated PD patients
who have a stable response to levodopa and do not experience motor complications.
DESIGN: Prospective, double-blind, placebo-controlled trial. SETTING:
Outpatient multicenter study.Patients Female and male patients 30 years
or older with idiopathic PD receiving stable doses of levodopa or carbidopa
with or without other dopaminergic therapies and who did not experience
motor fluctuations were eligible for the study. MAIN OUTCOME MEASURES:
Parkinsonian function and quality of life. RESULTS: The addition of entacapone
did not improve motor scores on the Unified Parkinson's Disease Rating
Scale in levodopa-treated PD patients who did not experience motor fluctuations.
The mean +/- SE adjusted change between baseline and final treatment visit
was -0.9 +/- 0.35 in the entacapone group and -0.8 +/- 0.35 in the placebo
group (P = .83). Significant improvement with entacapone treatment was
detected in several quality-of-life measures, including the Parkinson
Disease Questionnaire 39, the 36-item Short-Form Health Survey, the Parkinson's
Symptom Inventory, and investigator and subject Clinical Global Assessments.
The drug was well tolerated by patients in this population. CONCLUSIONS:
The catechol O-methyltransferase inhibitor entacapone, used as an adjunct
to levodopa in PD patients who do not experience motor fluctuations, does
not improve Unified Parkinson's Disease Rating Scale motor scores but
does improve a variety of quality-of-life measures.
Dev Med Child Neurol. 2004 Oct;46(10):710-2.
Pyruvate dehydrogenase deficiency presenting as dystonia in childhood.
Head RA, de Goede CG, Newton RW, Walter JH, McShane MA, Brown RM, Brown
GK.
Genetics Unit, Department of Biochemistry, University of Oxford, Oxford,
UK.
Two individuals with pyruvate dehydrogenase (PDH) deficiency due to missense
mutations in the gene for the E1alpha subunit (PDHA1) presented during
childhood with dystonia. The first patient, a male, presented at age 4
years with dystonia affecting the lower limbs, which responded to treatment
with combined carbidopa and levodopa. The second patient, a female, was
first investigated at age 6 years because of a dystonic gait disorder.
In both patients, the main clue to the biochemical diagnosis was a raised
concentration of lactate in the cerebrospinal fluid. PDH activity was
significantly reduced in cultured fibroblasts in both cases. Dystonia
is a previously unrecognized major manifestation of PDH deficiency and
is of particular interest as the mutations in the PDHA1 gene in these
patients have both been identified previously in individuals with typical
presentations of the condition.
Exp Neurol. 2004 Oct;189(2):369-79.
Rhythm-specific pharmacological modulation of subthalamic activity
in Parkinson's disease.
Priori A, Foffani G, Pesenti A, Tamma F, Bianchi AM, Pellegrini M, Locatelli
M, Moxon KA, Villani RM.
Department of Neurological Sciences, IRCCS Ospedale Maggiore di Milano,
Universita di Milano, 20122 Milan, Italy. alberto.priori@unimi.it
The subthalamic nucleus (STN) has a key role in the pathophysiology of
Parkinson's disease and is the primary target for high-frequency deep
brain stimulation (DBS). The STN rest electrical activity in Parkinson's
disease, however, is still unclear. Here we tested the hypothesis that
pharmacological modulation of STN activity has rhythm-specific effects
in the classical range of EEG frequencies, below 50 Hz. We recorded local
field potentials (LFPs) through electrodes implanted in the STN of patients
with Parkinson's disease (20 nuclei from 13 patients). After overnight
withdrawal of antiparkinsonian therapy, LFPs were recorded at rest both
before (off) and after (on) acute administration of different antiparkinsonian
drugs: levodopa, apomorphine, or orphenadrine. In the off-state, STN LFPs
showed clearly defined peaks of oscillatory activity below 50 Hz: at low
frequencies (2-7 Hz), in the alpha (7-13 Hz), low-beta (13-20 Hz), and
high-beta range (20-30 Hz). In the on-state after levodopa and apomorphine
administration, low-beta activity significantly decreased and low-frequency
activity increased. In contrast, orphenadrine increased beta activity.
Power changes elicited by levodopa and apomorphine at low frequencies
and in the beta range were not correlated, whereas changes in the alpha
band, which were globally not significant, correlated with the beta rhythm
(namely, low beta: 13-20 Hz). In conclusion, in the human STN, there are
at least two rhythms below 50 Hz that are separately modulated by antiparkinsonian
medication: one at low frequencies and one in the beta range. Multiple
rhythms are consistent with the hypothesis of multiple oscillating systems,
each possibly correlating with specific aspects of human STN function
and dysfunction.
J Neural Transm. 2004 Oct-Nov;111(10-11):1447-53.
Antiparkinsonian medication is not a risk factor for the development
of hallucinations in Parkinson's disease.
Merims D, Shabtai H, Korczyn AD, Peretz C, Weizman N, Giladi N.
Movement Disorders Unit, Department of Neurology, Tel Aviv Sourasky Medical
Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Background. It was commonly assumed that psychotic phenomena in Parkinson's
disease (PD) are mainly drug related. Accumulating evidence suggests the
existence of other risk factors for psychosis in PD. Aims. To evaluate
the contribution of the drug profile of patients with PD to emergence
of hallucinations. Methods. We compared patients with and without hallucinations,
using Cox proportional hazards model, concerning drug profile at the time
of hallucinations emergence. Results. Of 422 consecutive patients, 113
had dementia, while 90 patients experienced hallucinations (46 had both
dementia and hallucinations). The mean levodopa dose for the group of
patients with hallucinations was 650 +/- 279 mg/day at the time of hallucinations
onset, which was not significantly different from the levodopa dose at
last visit for the group without hallucinations (621 +/- 326 mg/day).
Supplementary treatment with amantadine, selegiline, dopamine agonists,
entacapone and anticholinergics did not increase the risk for the development
of hallucinations. Conclusions. We did not confirm drug treatment as a
risk factor for hallucinations in PD. Our study suggests the existence
of "endogenic" factors as substantial contributors in the genesis of PD
hallucinations. The clinical implications may be earlier administration
of antipsychotic treatment and not as traditionally accepted, dose reduction
of antiparkinsonian drugs.
J Neural Transm. 2004 Oct-Nov;111(10-11):1333-41. Epub 2004 May 12.
Effects of levodopa on cognitive functioning in moderate-to-severe
Parkinson's disease (MSPD).
Morrison CE, Borod JC, Brin MF, Halbig TD, Olanow CW.
Comprehensive Epilepsy, New York University Medical Center, New York,
NY, USA.
Although improved cognition has been reported in patients with mild Parkinson's
disease (PD) following the administration of levodopa, mixed results have
been found in moderately-to-severely affected PD patients (MSPD), particularly
in studies conducted since 1980. In the present study, 16 MSPD patients
were tested on separate days, once following overnight levodopa withdrawal
and once while optimally treated. A battery of neuropsychological tests
that assess a range of cognitive functions (i.e., attention, language,
visuospatial, memory, and executive), as well as a measure of depression,
were used. Although patients performed better on a measure of confrontation
naming in the untreated than in the treated condition, there were no significant
differences for any of the other cognitive variables or for the depression
scale variable. Thus, these data suggest that there are generally no adverse
or beneficial effects of levodopa therapy on cognition in MSPD patients.
J Neural Transm. 2004 Oct-Nov;111(10-11):1343-63. Epub 2004 Aug 03.
Clinical advantages of COMT inhibition with entacapone - a review.
Gordin A, Kaakkola S, Teravainen H.
Research Centre, Orion Pharma, Espoo, Finland.
Two catechol- O-methyltransferase (COMT) inhibitors, entacapone and tolcapone,
were developed during the 1990's to be used as adjuncts to levodopa (LD)
- dopa decarboxylase (DDC) inhibitors in the treatment of Parkinson's
disease (PD). Entacapone is currently in wide clinical use, while tolcapone
can be used in restricted indications only, due to its hepatotoxicity.
COMT inhibitors prolong the elimination of LD, while DDC inhibitors mainly
increase its absorption; both mechanisms leading to increased bioavailability
of LD. The pharmacokinetic properties of LD, carbidopa and entacapone
are quite similar, and entacapone is administered concomitantly with LD
plus carbidopa. Entacapone prolongs the clinical effect of each LD dose
by 30 to 40 minutes; this effect is seen already after the first entacapone
dose. When LD is administered in several frequent daily doses, addition
of entacapone reduces the daily fluctuations of plasma LD by 30 to 40%.Based
on studies with home diaries, entacapone increases the daily ON-time by
an average of one to two hours, and reduces the daily OFF-time correspondingly
in patients with PD with motor fluctuations. The daily LD dose has been
reduced by 10 to 30%. These positive effects are sustained in long term
use over several years. There is still scant information of the benefit
of entacapone in patients without motor fluctuations.Entacapone can cause
both dopaminergic and non-dopaminergic adverse events. Increased dyskinesias
are most frequently recorded in patients with motor fluctuations. The
dopaminergic adverse events can usually be diminished by reducing the
LD dose. Non-dopaminergic adverse events are abdominal pain and diarrhea.
Diarrhoea has led to discontinuation in 3 to 4% of the patients in clinical
trials. Entacapone has not been connected to liver toxicity and there
are no indications to follow laboratory safety during treatment. The benefit-risk
ratio of entacapone is considered favorable.A triple LD/carbidopa/entacapone
combination tablet has recently been developed. Three LD strengths (50,
100 and 150 mg) are available, each contains 200 mg of entacapone. The
majority of the patients can be managed with these three LD strengths.
Entacapone has today an established position in treatment of PD patients
with motor fluctuations, either as a separate tablet or as the triple
LD combination.
J Neurol Neurosurg Psychiatry. 2004 Oct;75(10):1382-5.
Efficacy of deep brain stimulation of the subthalamic nucleus in Parkinson's
disease 4 years after surgery: double blind and open label evaluation.
Rodriguez-Oroz MC, Zamarbide I, Guridi J, Palmero MR, Obeso JA.
Department of Neurology and Neurology, Neuroscience Center, Clinica Universitaria
and Medical School, Universidad de Novarra, 31008 Pamplona, Spain.
OBJECTIVE: To evaluate the long term (4 years) efficacy of deep brain
stimulation (DBS) of the subthalamic nucleus (STN) in advanced Parkinson's
disease. METHODS: We performed a double blind crossover evaluation of
the efficacy of DBS of the STN in the "off" medication condition in 10
patients with Parkinson's disease. Assessments included the Unified Parkinson's
Disease Rating Scale (UPDRS) part III (motor) and two timed tests (arm
tapping and walking). Open evaluation of the effect of stimulation in
the off and on drug states preoperatively and at 1 and 4 years postoperatively
was also conducted. The latter assessment included the UPDRS parts II
(activities of daily living) and III (dyskinesia scale and global assessment)
as judged by the patient and examiner. The mean amount of levodopa daily
dose at base line, 1 year, and 4 years after surgery was compared. RESULTS:
A significant (p<0.04) effect of stimulation was observed in the overall
group regarding both the UPDRS motor and the timed tests. Open evaluation
also showed a significant benefit of STN DBS with respect to preoperative
assessment in both the motor and activities of daily living scales, dyskinesia
scale, and in global assessment. Levodopa daily dose was reduced by 48%
and 50% at 1 and 4 years, respectively. There was no difference between
the 1 and 4 years evaluations in any of the parameters evaluated. Complications
due to stimulation were minor. CONCLUSIONS: DBS of the STN provides a
significant and persistent anti-parkinsonian effect in advanced Parkinson's
disease 4 years after surgery.
J Neurophysiol. 2004 Oct;92(4):1973-81. Epub 2004 Apr 28.
Discharge rate of substantia nigra pars reticulata neurons is reduced
in non-parkinsonian monkeys with apomorphine-induced orofacial dyskinesia.
Nevet A, Morris G, Saban G, Fainstein N, Bergman H.
Dept. of Physiology, The Hebrew University, Hadassah Medical School, P.O.
Box 12272, Jerusalem, 91120 Israel. alonevet@md.huji.ac.il
Involuntary movements (dyskinesia) are a common symptom of dopamine-replacement
therapy in parkinsonian patients, neuroleptic drug treatment of mental
patients, and tic disorders. Levodopa-induced dyskinesia has been shown
to be associated with substantial reduction of firing rate in the internal
part of the globus pallidus. This study characterizes the changes that
occur in the activity of the substantia nigra pars reticulata (SNr) of
non-parkinsonian (normal) monkeys with apomorphine (APO)-induced orofacial
dyskinesia. We conducted extracellular recordings of SNr neurons of two
monkeys before and after induction of orofacial dyskinesia by systemic
administration of APO. Involuntary orofacial movements appeared a few
minutes after the injections and lasted 20-40 min. Almost all recorded
neurons changed their firing rate after APO injection (96%), and most
declined (70%). The mean amplitude of decreases was also larger than that
of increases (40 vs. 21% of the control rate). Changes in firing pattern
were not significant on average. Pairs of SNr neurons were uncorrelated
before APO injection, similar to the normal pallidum. However, unlike
the increased correlations in the pallidum that accompany parkinsonism,
orofacilal dyskinesia in non-parkinsonian monkeys was not associated with
changes in correlation between SNr neurons. We conclude that normal monkeys
treated with APO can model orofacial dyskinesia and tic disorders that
are a consequence of dopaminergic over-activity. These symptoms appear
to be more related to reduced firing rate of SNr neurons and thus to disinhibition
of their targets, than to changes in pattern and synchronization.
J Neurosci Res. 2004 Oct 1;78(1):87.
Failure of neuronal protection by inhibition of glial activation in
a rat model of striatonigral degeneration.
Stefanova N, Mitschnigg M, Ghorayeb I, Diguet E, Geser F, Tison F, Poewe
W, Wenning GK.
Neurodegeneration Research Laboratory, Innsbruck MSA Study Group, Clinical
Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
Previous studies in rodent models of neurodegenerative disorders have
demonstrated that minocycline exerts neuroprotective effects unrelated
to its antimicrobial action. The purpose of the present study was to analyze
whether minocycline exhibits neuroprotective activity in a rat model of
striatonigral degeneration (SND), the core pathology underlying levodopa-unresponsive
parkinsonism associated with multiple system atrophy (MSA). We observed
no significant effect of minocycline on locomotor impairment in double-lesioned
SND rats. Minocycline significantly suppressed astroglial and microglial
activation (P < 0.01); however, 3'5'-monophosphate-regulated phosphoprotein
(DARPP 32) immunohistochemistry revealed no significant differences in
striatal lesion volume of minocycline-treated versus untreated control
SND rats. Furthermore, there was no protection of nigral dopaminergic
neurons in the double-lesion model. We conclude that despite its astrocytic
and microglial suppression, minocycline failed to attenuate lesion-induced
neuronal damage in the SND rat model. Copyright 2004 Wiley-Liss, Inc.
Mov Disord. 2004 Oct;19(10):1183-6.
Effect of monoamine reuptake inhibitor NS 2330 in advanced Parkinson's
disease.
Bara-Jimenez W, Dimitrova T, Sherzai A, Favit A, Mouradian MM, Chase TN.
Experimental Therapeutics Branch, National Institute of Neurological Disorders
and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
Dopamine reuptake blockers, by enhancing and stabilizing intrasynaptic
transmitter levels, could help palliate motor dysfunction in Parkinson's
disease. This randomized, double-blind, placebo-controlled study compared
the acute effects of the monoamine uptake inhibitor NS 2330 to those of
placebo in 9 relatively advanced parkinsonian patients. At the dose administered,
no change in parkinsonian scores was found when NS 2330 was given alone
or with levodopa. Moreover, NS 2330 coadministration did not appear to
alter dyskinesia severity or the duration of the antiparkinsonian response
to levodopa. The drug was well tolerated. Under the conditions of this
study, the present results failed to support the usefulness of dopamine
reuptake inhibition in the treatment of advanced Parkinson's disease.
(c) 2004 Movement Disorder Society.
Mov Disord. 2004 Oct;19(10):1232-6.
L-dopa-responsive Parkinson's syndrome in association with phenylketonuria:
In vivo dopamine transporter and D2 receptor findings.
Evans AH, Costa DC, Gacinovic S, Katzenschlager R, O'sullivan JD, Heales
S, Lee P, Lees AJ.
Reta Lila Weston Institute of Neurological Studies, University College
London.
Reports of parkinsonism in phenylketonuria are exceedingly rare. We report
on a patient who had received a delayed diagnosis of phenylketonuria as
an infant and subsequently developed levodopa-responsive parkinsonism
at the age of 33. Single-photon emission computed tomography (SPECT) using
(123)I-FP-CIT ([(123))I]-2 beta-carbomethoxy-3beta-(-4-iodophenyl)-N-(3-fluoropropyl)-nortropane)
used to measure dopamine transporter levels on two occasions, 7 and 9
years after the onset of neurological symptoms, were normal. Iodine-123-iodo-lisuride
SPECT (IBZM) imaging, however, showed reduced caudate over putamen binding.
This combination of imaging findings indicates a possible upregulation
of postsynaptic D2 receptors in the context of intact presynaptic dopamine
nerve terminal density. (c) 2004 Movement Disorder Society.
Mov Disord. 2004 Oct;19(10):1256-8.
Amantadine for levodopa-induced choreic dyskinesia in compound heterozygotes
for GCH1 mutations.
Furukawa Y, Filiano JJ, Kish SJ.
Movement Disorders Research Laboratory, Centre for Addiction and Mental
Health-Clarke Division, Toronto, Ontario, Canada.
Amantadine suppressed severe levodopa-induced choreic dyskinesia, which
developed at initiation of levodopa therapy, in two siblings manifesting
dystonia with motor delay phenotype of GTP cyclohydrolase I deficiency
caused by compound heterozygous GCH1 mutations. Our finding suggests a
beneficial effect of amantadine on this type of dyskinesia frequently
observed in relatively severe dopamine-deficient metabolic disorders.
(c) 2004 Movement Disorder Society.
Tidsskr Nor Laegeforen. 2004 Jan 8;124(1):25-7.
Restless legs syndrome.
Kinge E, Lossius MI.
Sandvika Nevrologpraksis, 1338 Sandvika.
Restless legs syndrome is a common and not fully appreciated disorder.
Improved treatment options require knowledge about the condition.
Material and methods.The article is based on a literature search on Medline,
PubMed and Scirus for the years 1988 - 2003 with the keyword "restless
legs".
Results and interpretation. Restless legs syndrome is a chronic condition
defined as an irresistible desire to move one's limbs, usually associated
with paraesthesia/dysaesthesia and motor restlessness. The symptoms start
or worsen at rest and improve with activity. The prevalence is between
5 % and 15 %. 80 % of patients suffer from periodic limb movements in
sleep. A current hypothesis is that the condition results from a deficiency
of iron that lead to the underlying dopaminergic abnormalities. Therapeutically,
studies have confirmed the effect of levodopa and dopamin agonists; dopamin
agonists seem to imply less risk of side effects.
Rev Neurol. 1997 Dec;25(148):1957-63.
Leiva C.
Servicio de Neurologia, Hospital General Universitario de Alicante, Espana.
Madopar: more than 20 years
To review the main landmarks which led to the introduction of levadopa
in the the treatment of Parkinson's disease and the impact of levadopatherapy.
The introduction of levadopa was based on the results of basic scientific
investigations in neurochemistry and neuropharmacology. In 1959 the possibility
of dopamine being a neurotransmissor, and the role it plays in motor control,
had been discovered. In 1960, Hornykiewiez and Ehringer published a paper
on the existence of a marked deficit of dopamine in the caudate nucleus
and putamen of patients with Parkinson's disease. Almost simultaneously,
Birkmayer and Barbeau treated their patients with levadopa for the first
time. However, levadopa was not introduced into clinical practice until
1967 and 1969 when Cotzias published papers establishing the principles
of levadopatherapy as we now know it. Introduction of levadopa produced
a markedly beneficial effect on the course and mortality of Parkinson's
disease. However, it was soon seen that progression of the disease was
not halted and that undesirable side effects appeared in patients on long-term
treatment. This has led to the development of strategies to prolong the
beneficial effects of levadopa and minimize its side effects. CONCLUSION:
More than 25 years after the introduction of levadopatherapy, it is still
the mainstay of the treatment of Parkinson's disease, in combination with
other medical and surgical treatment. Definitive treatment, however, will
have to wait until the cause of this illness is fully understood.
Zh Nevrol Psikhiatr Im S S Korsakova. 2000;100(12):46-8.
Vendrova MI, Sadekov RA, Golubev VL.
Efficiency of new forms of madopar in Parkinson's disease
The paper presents estimation of the efficiency of some new forms of madopar
(madopar dispergative--Mad-Dis, Mad-HBS) in 26 patients with Parkinson's
disease by methods of motor potential, autonomic tests. A good tolerance
of Mad-HBS was found. Its administration neither causes changes of autonomic
indices nor aggravates symptomatology of cardiovascular disease. A single
dose of Mad-Dis may serve as a predictor for a positive result of DOPA-containing
preparations in a certain group of patients with Parkinson's disease.
Pharmacology. 1994 Apr;48(4):226-33.
Himori N, Tanaka Y, Kurasawa M, Mishima K, Akaike N.
Department of Pharmacology, Nippon Roche Research Center, Kamakura, Japan.
3-O-methyldopa attenuates the effects of Madopar on the haloperidol-induced
cataleptic behavior and the locomotor activity in the mouse.
The effects of Madopar (levodopa plus benserazide) on the cataleptic behavioral
response to haloperidol and on the locomotor activity in mice were quantitatively
compared before and after the administration of 3-O-methyldopa (3OMD).
The intraperitoneal administration of 3OMD (200-400 mg/kg) alone did not
modify the haloperidol (1.0 mg/kg s.c.)-induced catalepsy. Madopar, depending
on the dose regimen, markedly antagonized the haloperidol-induced catalepsy.
Pretreatment with 3OMD tended to reverse the antagonistic property of
Madopar on the cataleptic behavior in response to haloperidol. The ability
of 3OMD to significantly inhibit Madopar effects was observed in the locomotor
testing paradigm; the locomotor hyperactivity in Madopar-treated animals
was significantly inhibited by a prior intraperitoneal injection of 3OMD.
The results from our animal experiments may provide further evidence that
impediment of 3OMD formation is meaningful in the treatment of Parkinson's
disease with Madopar or levodopa.
Zhonghua Yi Xue Za Zhi (Taipei). 1996 Oct;58(4):264-8.
Shan DE, Yeh SI.
Neurology, Neurological Institute, Veterans General Hospital-Taipei, Taiwan,
R.O.C.
An add-on study of selegiline to Madopar in the treatment of parkinsonian
patients with dose-related fluctuations: comparison between Jumexal and
Parkryl.
To improve dose-related fluctuations in patients with Parkinson's disease,
the efficacy of selegiline, a selective inhibitor of monoamine oxidase
B, was determined. Twenty parkinsonian patients were selected for a short-term,
single-blind, cross-over trial. Each patient received one of the two brands
of selegiline, Parkryl (Mei-Shih), 10 mg per day as an adjunct to Madopar.
After a 6-week treatment period and a 4-week wash-out period, the treatment
was switched to the other brand of selegiline, Jumexal (Labatec), for
another 6 weeks. Five patients dropped out of the study because of the
development of intolerable dyskinesia, hallucination or agitation. The
15 patients that completed the study made a mild improvement in the total
motor scores of the on-period during both treatments of Parkryl (p <
0.01) and of Jumexal (p < 0.05). The recorded daily off-time decreased
from 37.8% to 20.7% in the Parkryl group (p < 0.01), and to 21.0% in
the Jumexal group (p < 0.01). Selegiline, as an adjunct therapy to
Madopar, has a moderate effect in prolonging the duration of on-time in
parkinsonian patients with dose-related fluctuations. Jumexal seemed to
produce no greater effect than Parkryl.
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Madopar
(Levodopa)
