J Commun Disord. 2005
May-Jun;38(3):187-96. Epub 2004 Nov 10.
The effects of levodopa on word intelligibility in Parkinson's disease.
De Letter M, Santens P, Borsel JV.
Department of Oto-Rhino-Laryngology, Ghent University Hospital,
De Pintelaan 185, B-9000 Ghent, Belgium.
Dysarthria is a common manifestation in patients
with idiopathic Parkinson's disease. This study investigated the
effects of levodopa on intelligibility in patients with Parkinson's
disease. Ten participants were tested during on- and off-states
using the Yorkston and Beukelman intelligibility test (1980).
Intelligibility as scored by a panel of speech therapists was
significantly improved in the on-condition. No correlation was
found, however, between intelligibility and overall severity of
the disease or severity of the motor problems. EDUCATIONAL OUTCOMES::
As a result of this activity the participant will be able to discuss
the effects of levodopa on intelligibility in patients with Parkinson's
disease.
J Pain Symptom Manage. 2003 Apr;25(4):386-90.
Treatment of tremors in complex regional pain syndrome.
Navani A, Rusy LM, Jacobson RD, Weisman SJ.
Department of Anesthesiology, Children's Hospital and Medical
College of Wisconsin, Milwaukee, WI, USA.
A 14-year-old girl presented with Complex Regional
Pain Syndrome, Type I (CRPS-1) of the left ankle after a remote
history of sprain. Allodynia, pain, temperature and color changes,
and swelling were successfully treated with physical therapy,
transcutaneous electrical nerve stimulation (TENS), gabapentin,
amitriptyline, and tramadol. Five weeks later, she presented with
a continuous, involuntary, intermittent coarse tremor of the left
foot causing increased pain. The electromyogram showed rhythmic
discharges of 3 Hz frequency lasting 20-80 milliseconds in the
left tibialis, peroneus and gastrocnemius, suggestive of either
basal ganglia or spinal origin. Tremor and pain were controlled
with epidural bupivacaine, but the tremor reappeared after discontinuing
epidural blockade. Carbidopa/levodopa 25/100 (Sinemet) was started
and the tremor disappeared after two days. With continued physical
therapy, pain and swelling resolved within two months and carbidopa/levodopa
was discontinued after five weeks with no recurrence of the tremor.
Our success in the treatment of CRPS-associated tremor in this
young girl with carbidopa/levodopa suggests that this patient
may have had underlying movement disorder which was unmasked by
the peripheral injury.
Ann Neurol. 2003;53 Suppl 3:S87-97; discussion S97-9.
Neuroprotection in Parkinson's disease: clinical trials.
Stocchi F, Olanow CW.
Department of Neuroscience and Neuromed, University La Sapienza,
Rome, Italy.
Advances in our understanding of the cause and
pathogenesis of Parkinson's disease (PD) have permitted the rational
selection of putative neuroprotective agents for study in PD.
However, the list of agents that might provide neuroprotective
effects derived from laboratory studies is daunting, and we face
the challenge of determining which agents to bring to the clinic
and how to find the resources (patients and funds) to properly
study so many promising therapeutic opportunities.1 Appropriate
outcome variables that are not confounded by any symptomatic effect
of the drug and are acceptable to clinicians and regulatory authorities
also remain to be defined. The first clinical trials designed
to test the capacity of putative neuroprotective agents to alter
the natural history of PD have now been performed and illustrate
some of these problems. The DATATOP (Deprenyl and Tocopherol Antioxidant
Therapy of PD) study used the time to reach a disease milestone
in untreated PD patients (ie, need for levodopa) as the primary
end point. However, interpretation of results was confounded by
the drug's symptomatic effect. The SINDEPAR (Sinemet-Deprenyl-Parlodel)
study used the change in motor score between initial visit and
final visit after washout of all study medications as the primary
end point. However, here too there were concerns about confounding
symptomatic effects, because antiparkinsonian medications have
now been shown to have a long duration response that can persist
for weeks and perhaps even months after withdrawal. More recent
studies have used surrogate markers of the integrity of nigrostriatal
function such as striatal uptake of fluorodopa on positron emission
tomography (PET) or beta-CIT-on single-photon emission computerized
tomography (SPECT) as primary outcome measures. However, it has
not yet been confirmed that striatal uptake of these isotopes
does in fact correlate with the remaining number of dopamine neurons
or terminals, and the possibility of a confounding pharmacological
effect has not yet been completely excluded. To date, no drug
has been established to have a neuroprotective effect in PD, and
none has been approved for a neuroprotective indication. Furthermore,
regulatory agencies have not yet agreed that any of the outcome
measures currently used will be acceptable for approval of a new
drug. Resolution of these issues is of critical importance to
convince pharmaceutical companies to expend the hundreds of millions
of dollars necessary to bring a new drug to market. Drugs that
already have been approved in PD for their symptomatic effects,
such as dopamine agonists or propargylamines (eg, selegiline),
offer the best opportunity for establishing that a drug is neuroprotective
in PD in the immediate future, but herein also lies the difficulty
of establishing that any benefits observed are not solely because
of the drug's symptomatic properties. Currently, this will most
likely entail demonstrating that the drug provides benefit for
PD patients for both imaging and clinical markers of disease progression.
Acta Neurol Scand. 2004 Sep;110(3):188-95.
Levodopa effect on [F]fluorodopa influx to brain: normal volunteers
and patients with Parkinson's disease.
Kumakura Y, Danielsen EH, Reilhac A, Gjedde A, Cumming P.
PET Centre, Aarhus University Hospitals and Centre for Functionally
Integrated Neuroscience, Aarhus.
Kumakura Y, Danielsen EH, Reilhac A, Gjedde A, Cumming P. Levodopa
effect on [(18)F]fluorodopa influx to brain: normal volunteers and
patients with Parkinson's disease. Acta Neurol Scand 2004 DOI: 10.1111/j.1600-0404.2004.00299.x
Copyright Blackwell Munksgaard 2004.Objectives - Levodopa is the
immediate precursor of dopamine and the substrate for DOPA decarboxylase,
an enzyme subject to regulation in living brain. To test whether
this regulation changes in disease, we used Positron Emission Tomography
(PET) with parametric mapping to measure the effect of levodopa
on the net clearance of [(18)F]fluorodopa to brain (K, ml/g/min).
Methods - Five patients with early Parkinson's disease with pause
of medication for 3 days and six age-matched healthy volunteers
were studied in a baseline condition and after levodopa challenge.
Results - Levodopa (200 mg as Sinemet) increased the magnitude of
the net clearance K in the left and right putamen of the healthy
volunteers by 11% relative to the baseline condition. In contrast,
resumption of medication with levodopa did not significantly alter
the magnitude of K in putamen of the Parkinson's disease patients.
Compartmental analysis was used to probe the physiological basis
of the activation of K: levodopa treatment increased by 15% the
apparent distribution volume of [(18)F]fluorodopa in cerebellum
(, ml/g) of both patients and control subjects, without significantly
altering the unidirectional blood-brain clearance (, ml/g/min) or
the relative activity of DOPA decarboxylase (, min(-1)) in putamen.
Conclusion - We conclude that levodopa treatment increases the distribution
volume of [(18)F]fluorodopa in brain, increasing its availability
for utilization in dopamine terminals. We speculate that levodopa
act as a direct beta-adrenergic agonist at receptors regulating
the permeability of the blood-brain barrier to levodopa. However,
the PET analytical method was without sufficient power to detect
the consequent increase in magnitude of K in brain of only five
Parkinson's disease subjects.
Rev Med Chil. 2003 Jun;131(6):623-31.
Pharmacokinetic comparison of Sinemet and Grifoparkin (levodopa/carbidopa
250/25 mg) in Parkinson s disease: a single dose study.
Chana P, Fierro A, Reyes-Parada M, Saez-Briones P.
Unidad de Movimientos Anormales, Servicio de Neurologia y Neurocirugia,
Hospital DIPRECA.
BACKGROUND: There are doubts wether generic medications have the
same bioavailability and efficacy compared with the original drugs
developed by pharmaceutical companies with research capabilities.
AIM: To compare the pharmacokinetics and clinical (motor) responses
of Sinemet and Grifoparkin (generic carbidopa/levodopa 250/25
mg) in patients with advanced Parkinson's disease. PATIENTS AND
METHODS: Patients were randomly assigned to Sinemet (15 patients
62 +/- 12 years old; mean disease duration 11 +/- 7 years) or
Grifoparkin (15 patients, 64 +/- 11 years old; mean disease duration
12 +/- 4 years) groups. Medication and food were withheld 12 h
before the study. Fifteen blood samples were collected (starting
9 AM) immediately before (sample 1, t = 0 min) and after (samples
2-15, t = 20-360 min) oral administration of a single dose of
Sinemet or Grifoparkin, and plasmatic L-DOPA was quantified using
HPLC with electrochemical detection. Additionally, each patient
was clinically evaluated every 20 minutes, using the tapping test
and the unified Parkinson's disease scale Hoehn & Yarh. RESULTS:
Tmax (time at which the maximal L-DOPA concentration was reached)
were 69 +/- 12 min and 64 +/- 11 min for Sinemet and Grifoparkin
respectively (NS). Cmax (maximal L-DOPA concentration reached)
was 3161 +/- 345 ng/ml for Sinemet and 3274 +/- 520 ng/ml for
Grifoparkin (NS). The t1/2 (half life time), CL (clearance) and
volume of distribution (Vd) values calculated were 159 +/- 32
min, 51.7 +/- 5.1 1/h and 3.6 +/- 1.2 l/kg for Sinemet and 161
+/- 48 min, 58.7 +/- 8 l/h and 3.0 +/- 0.7 l/kg for Grifoparkin
(NS). UPDRS-III value for the best "on state" and for
the worst "off state" were 23 +/- 11 and 50 +/- 19 for
Sinemet and 20 +/- 7 and 46 +/- 13 for Grifoparkin respectively
(NS). CONCLUSION: The results obtained showed that both drugs
are bioequivalent in patients with advanced Parkinson's disease.
Mov Disord. 1999 Nov;14(6):940-6.
The effect of dopamine agonist therapy on dopamine transporter
imaging in Parkinsons disease.
Ahlskog JE, Uitti RJ, OConnor MK, Maraganore DM, Matsumoto JY,
Stark KF, Turk MF, Burnett OL.
Department of Neurology, Mayo Clinic, Rochester, Minnesota 55905,
USA.
Single-photon emission computed tomography (SPECT) imaging with
the dopamine transporter ligand, [123I] beta-CIT (2beta-carboxymethoxy-3beta-[4-iodophenyl]
tropane), has been proposed as a means of measuring Parkinson's
disease (PD) progression. To be useful in this role, however,
[123I] beta-CIT imaging should not be influenced by the medications
used to treat PD, including the dopamine agonist drugs such as
pergolide. We assessed the effect of adjunctive pergolide administration
on [123I] beta-CIT uptake in 12 patients with PD, who were being
treated with levodopa, initiating pergolide therapy for motor
fluctuations. Patients underwent [123I] beta-CIT imaging at baseline,
subsequently while on pergolide therapy (6 weeks), and again 4
weeks after pergolide wash-out. Uptake in the striatum was averaged
for the two sides and expressed as (striatum - occipital)/occipital,
with similar calculations for putamen and caudate. Consistent
with PD, the patients' mean striatal and putamen uptake ratios
at baseline were significantly less (p <0.001) than the mean
values from 26 normal control subjects of similar age. During
pergolide treatment, the striatal and putamen [123I] beta-CIT
uptake ratios were each statistically similar to baseline, although
there was a slight trend toward an increased striatal value (8%
higher on pergolide; p = 0.105). Caudate [123I] beta-CIT uptake
was 11% higher on pergolide therapy (nominal p = 0.042, but not
significant when adjusted for multiple comparisons: p = 0.126).
After pergolide wash-out, the striatal, putamen, and caudate uptake
ratios did not differ from baseline. Therefore, we found that
pergolide therapy did not significantly affect [123I] beta-CIT
SPECT imaging but we cannot exclude a small influence.
Clin Neuropharmacol. 1999 Jan-Feb;22(1):33-9.
Evaluation of equivalent efficacy of sinemet and sinemet CR in
patients with Parkinson's disease applying levodopa dosage conversion
formula.
Manyam BV, Hare TA, Robbs R, Cubberley VB.
Department of Neurology, Southern Illinois University School of
Medicine, Springfield 62794-1316, USA.
We report ease of conversion, effect on equivalent efficacy and
frequency of dosing when immediate-release carbidopa/levodopa
(Sinemet, IR-CL, DuPont Pharma, Wilmington, DE, U.S.A.) is replaced
with controlled-release carbidopa/levodopa (Sinemet CR, CR-CL,
DuPont Pharma, Wilmington, DE, U.S.A.) in patients with Parkinson's
disease (PD). One-step conversion through the application of a
mathematical formula was utilized. Fifty-two patients (35 men,
17 women) with a mean +/- SD age of 72 +/- 8 years participated
in this open-label study. All patients were taking IR-CL prior
to conversion. The Unified Parkinson's Disease Rating Scale (UPDRS)
was used for efficacy assessment. Pharmacokinetic studies were
undertaken in five patients while they were on IR-CL, and repeated
after they were switched to CR-CL. Dosage adjustment was not required
either immediately after converting or during the 6-month follow-up.
No significant changes occurred in efficacy scores during follow-up
visits, indicating the effectiveness of the conversion. There
were substantial differences in the level of plasma DOPA, dopamine,
3-O-methyldopa, homovanillic acid, and dihydroxyphenylacetic acid
between patients receiving IR-CL and those receiving CR-CL, but
the differences did not correlate with clinical changes, suggesting
that plasma levels do not reflect tissue levels at the site of
action for levodopa. This study demonstrates that conversion from
IR-CL to CR-CL for optimal dosing may be achieved in one step
through the application of a mathematical formula with ease of
conversion and reduction of number of doses.
Ann Pharmacother. 1998 Sep;32(9):878-83.
Pharmacoeconomic analysis of using Sinemet CR over standard Sinemet
in parkinsonian patients with motor fluctuations.
Hempel AG, Wagner ML, Maaty MA, Sage JI.
College of Pharmacy, Rutgers, State University of New Jersey,
Piscataway 08854, USA.
OBJECTIVE: To compare the costs of pharmacotherapy in patients
with Parkinson's disease before and after converting from standard
Sinemet to extended-release Sinemet CR. DESIGN: Investigators
retrospectively reviewed records of patients converting from Sinemet
to Sinemet CR for efficacy and total drug costs. Cost-effectiveness
was evaluated retrospectively from data collected in prospective
Sinemet CR efficacy trials. SETTING: Parkinson's disease clinic
at a tertiary care university teaching hospital. PATIENTS: 100
patients with motor fluctuations who had undergone an initial
6-month course of Sinemet therapy, followed by a 6-month course
of Sinemet CR. MAIN OUTCOME MEASURES: Total cost was measured
as the cost of Sinemet formulations plus the costs of other antiparkinson
medications. Differences in pre- and postconversion costs were
compared by using the paired, two-tailed Student's t-test. A substudy
of 39 patients on the cost-effectiveness of conversion measured
the ratio of daily medication costs to the daily hours "on"
without chorea. RESULTS: While total daily medication costs after
conversion increased by 21%, patients experienced either a comparable
or an improved degree of disease control with Sinemet CR. Patients
who were also taking selegiline were able to decrease selegiline
expense by 20%. The costs of other adjunctive medications did
not differ significantly after conversion. The cost-effectiveness
analysis revealed an increase in postconversion on time by 2.2
hours (p = 0.0001), accompanied by a $2.85 decrease in total cost
per hour on without chorea (p = 0.11). CONCLUSIONS: Although Sinemet
CR is more costly, it may be more cost-effective in patients with
motor fluctuations. Some patients may be able to reduce adjunctive
medications.
J Neural Transm Park Dis Dement Sect. 1990;2(3):205-13.
Results of long-term treatment with controlled-release levodopa/carbidopa
(Sinemet CR).
Cedarbaum JM, Silvestri M, Clark M, Toy L, Harts A, Green-Parsons
A, McDowell FH.
Department of Neurology and Neuroscience, Cornell University Medical
College, New York, NY.
35 Parkinson's disease patients with motor response fluctuations
(RF) participated in controlled clinical trials comparing Sinemet
CR to Standard Sinemet (STD) at our institutions. 13 of 25 eligible
patients continued to two years (the longest possible follow-up
from the second study), and 5 of 11 have continued taking CR up
to 4 years. At the end of both two and four years, patients were
taking significantly fewer medication doses, with a significantly
longer interdose interval, and up to two years, experienced fewer
"off" periods than when on Standard Sinemet (STD) alone.
Most patients required STD at at least one dose each day to hasten
to onset of antiparkinson effect. Sinemet CR is a useful adjunct
in the long-term management of motor response fluctuations in
Parkinson's disease.
Neurology. 1989 Nov;39(11 Suppl 2):25-38.
Pharmacokinetics and bioavailability of Sinemet CR: a summary
of human studies.
Yeh KC, August TF, Bush DF, Lasseter KC, Musson DG, Schwartz S,
Smith ME, Titus DC.
Department of Drug Metabolism, Merck Sharp & Dohme Research
Laboratories, West Point, PA 19486.
The pharmacokinetics of Sinemet CR, a controlled-release formulation
containing carbidopa and levodopa, were investigated in healthy
young and elderly volunteers and in patients with Parkinson's
disease. Sinemet CR produced more sustained plasma levels of levodopa,
carbidopa, and 3-O methyldopa than did conventional Sinemet. In
elderly subjects, the corresponding steady-state plasma levels
fluctuated in narrower ranges with Sinemet CR than those following
the administration of Sinemet. Results indicate a levodopa bioavailability
of 71% for Sinemet CR, in contrast to a bioavailability of 99%
for Sinemet for these subjects. The carbidopa bioavailability
of Sinemet CR was 58% relative to that of Sinemet. Systemic decarboxylase
inhibition was comparable between the 2 regimens as indicated
by the renal clearance of levodopa. The absorption of levodopa
was slower and more protracted with Sinemet CR than with Sinemet.
Food increased the levodopa bioavailability of Sinemet CR. This
increase was attributed to an increased gastric retention time.
No dose-dumping occurred with Sinemet CR in either the nonfasting
or the fasting state. Levodopa bioavailability was lower in young
volunteers than in elderly volunteers. This was attributed to
an age-related decrease in gastric emptying and in 1st-pass metabolic
decarboxylation in the gastrointestinal (GI) tract. In parkinsonian
patients, as in healthy subjects, the Sinemet CR formulation produced
more sustained levodopa plasma levels. These patients required
a higher total daily dosage of Sinemet CR than of Sinemet for
control of parkinsonian symptoms, but less frequent dosing was
required during chronic therapy. Peak plasma levodopa levels increased
proportionately with increasing Sinemet CR dosage. These observations
were consistent with the pharmacokinetic characteristics of the
formulation.
J Neurol. 1998 May;245 Suppl 1:S31-3.
Quality of life in patients with Parkinsons disease who transfer
from standard levodopa to Sinemet CR: the STAR Study. The STAR
Multicenter Study Group.
Grandas F, Martinez-Martin P, Linazasoro G.
Servicio de Neurologia, Hospital General Universitario Gregorio
Maranon, Madrid, Spain.
Conversion from standard levodopa to Sinemet CR was performed
in a series of 450 patients with Parkinson's disease. Of these,
299 experienced motor complications (group A) and 151 showed stable
motor response (group B). There was significant improvement in
various parameters of efficacy (Unified Parkinson's Disease Rating
Scale, Hoehn-Yahr staging, Schwab-England scale) particularly
in those related to functional aspects such as activities of daily
living of the Unified Parkinson's Disease Rating Scale, sleep
questionnaires and the Nottingham Health Profile. Adverse effects
were usually mild or moderate, and only 10% of patients discontinued
Sinemet CR due to side effects. Sinemet CR treatment was preferred
by 81% of patients in group A and by 73.8% of patients in group
B.
Arch Phys Med Rehabil. 1995 Sep;76(9):868-70.
Use of Sinemet in locked-in syndrome: a report of two cases.
Ockey RR, Mowry D, Varghese G.
Department of Rehabilitation Medicine, University of Kansas Medical
Center, Kansas City 66103, USA.
Locked-in syndrome describes a neurological condition usually
associated with infarction of the ventral pons. Such patients
are diagnosed with quadriplegia, lower cranial nerve paralysis,
and mutism. The patient is alert but communication is severely
limited and usually is accomplished by blinking or using vertical
eye movements. The rehabilitative management of locked-in syndrome
has consisted of preventative and supportive measures. In this
study we report two cases of locked-in syndrome which were treated
successfully with Sinemet (DuPont Pharmaceuticals, Wilmington,
DE). Even though the exact neuropharmacological mechanism is unclear,
the dramatic improvement in these cases, as well as in one other
published case report, dictates that use of Sinemet should be
considered in the management of locked-in syndrome.
Zh Nevropatol Psikhiatr Im S S Korsakova. 1995;95(5):31-5.
The use of the Sinemet-CR preparation in treating Parkinsons disease
Artemev DV, Damulin IV, Iakhno NN.
Sinemet-CR is manufactured by "Merck, Sharp and Dohme"
firm (USA). It is represented the tablet form of drug that consists
of levodopa (200 mg) and carbidopa (50 mg) on polymeric basis.
This basis is dissolved gradually in small intestine providing
prolonged drug's action. 29 patients in the age of 38-77 years
with different forms of Parkinson's disease (1-13 years of duration)
were treated using the doses 500-1500 mg. The doses depended upon
both disease stage and individual sensitivity. It was also taken
into consideration if the patients were or were not treated with
levodopa and carbidopa preparations previously (the dose was adjusted
during 3-4 weeks). The treatment's duration was 3 months. The
positive medical effect was revealed in 23 cases (80%) while more
expressed and firm effect was obtained in 15 cases. The most manifested
action was observed toward rigidity, hypokinesia and tremor as
well as toward such functions as memory, attention and psychical
activity. Preparation's negative action was registered in 6 observations.
In conclusion the authors noted both the high effectiveness and
safety of preparation and recommended it for wide application.
Neurology. 1992 Jan;42(1 Suppl 1):44-50; discussion
57-60.
The use of Sinemet CR in the management of mild to moderate Parkinsons
disease.
Rodnitzky RL.
Department of Neurology, College of Medicine, University of Iowa,
Iowa City.
The pharmacokinetic advantage of controlled-release carbidopa-levodopa
(Sinemet CR) is its slow dissolution and gradual absorption, resulting
in more sustained plasma levodopa levels and higher plasma troughs.
In patients with moderately severe disease, the benefits include
less severe "wearing-off," a modest increase in daily
"on" time, and fewer daily doses. Bioavailability of
Sinemet CR levodopa is less than that of standard Sinemet, so
a slightly higher total daily levodopa dose is required to achieve
a comparable effect; but because Sinemet CR is absorbed much more
slowly than is the standard preparation, dosing frequency can
be reduced by up to half. For most patients, titration will be
required after the transition has been made from standard to controlled-release
Sinemet. The effect of Sinemet CR on dyskinesias is often difficult
to predict and, in individual patients, may depend on the temporal
pattern of dyskinesias being experienced. Success in using this
new preparation depends on understanding its pharmacokinetic properties,
judicious patient selection, and an effective program of patient
education.
Can J Neurol Sci. 1991 Nov;18(4):467-71.
Long-term evaluation of Sinemet CR in parkinsonian patients with
motor fluctuations.
Hutton JT, Morris JL.
Parkinsons Disease Research Center, St. Mary of the Plains Hospital,
Lubbock, Texas 79410.
The safety and efficacy of Sinemet CR, a controlled-release formulation
of carbidopa/levodopa, were investigated in a three year, open-label
trial involving 18 parkinsonian patients with fluctuating motor
response. The average daily levodopa dosing frequency did not
change significantly during long-term treatment. Efficacy measures
generally revealed a gradual progression of parkinsonian disability.
Patient diaries of motor fluctuations revealed relative stability
of time "on" but with a tendency toward increased time
"on with dyskinesias" over the 36 month follow-up period.
There were no adverse laboratory results deemed to be related
to Sinemet CR and no unexpected side effects were observed.
