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Duodenal delivery of levodopa for on-off fluctuations in parkinsonism Preliminary observations.

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20. Phelps ME, Hoffman EJ, Huang SC: ECAT: a new computerised tomographic imaging system for positron emitting
ndiopharmaceuticds.J Nucl Med 19:635-647, 1978
21. Pran OE: Transport inhibition in the pathology of phenylketonuria and other inherited metabolic diseases. J Inher Metab
Dis 5:75-81, 1982.
22. Wade LA, Kanman R: Synthetic amino acids and the nature of
L-dopa transport at the blood-brain-barrier. J Neurochem
25:a3~-842,1975
Duodenal Delivery
of Levodopa for
On-Off Fluctuations
in Yarkmsonism:
Preliminary Observations
Roger Kurlan, MD, Allen J. Rubin, MD,
Charlyne Miller, RN, MS, Leonor Rivera-Calimlim, MD,
Allan Clarke, BS, and Ira Shoulson, M D
The pathogenesis of on-off motor fluctuations in parkinsonism remains incompletely understood, but slowed or
erratic gastric emptying of orally administered levodopa
may be involved. In 3 patients with resistant on-off
fluctuations, direct duodenal continuous infusion of
levodopa via a nasoduodenal tube resulted in a heightened therapeutic effect, including a reduction in motor
fluctuations. In 1of these patients, continuous duodenal
levodopa infusion produced greater benefit than did intermittent duodenal levodopa administration. Direct
duodenal delivery of levodopa lessens the problems with
gastric emptying and may be suitable for long-term
therapy in selected patients with resistant on-off motor
fluctuations.
Kurlan R, Rubin AJ, Miller C , Rivera-Calimlim L,
Clarke A, Shoulson I: Duodenal delivery
of levodopa for on-off fluctuations
in parkinsonism: preliminary observations.
Ann Neurol20:262-265, 1986
Fluctuations in motor performance remain a major
problem in the long-term care of levodopa-treated patients with Padunson’s disease [ 8 ] . The pathogenesis
of on-off fluctuations remains incompletely under-
From the Departments of Neurology and Pharmacology, University
of Rochester School of Medicine, Rochester, N Y 14642.
Received Sept 30, 1985, and in revised form Nov 26. Accepted for
publication Dec 21, 1985.
Address reprint requests to Dr Kurlan.
262
stood. Both pharmacoktnetic factors determining the
delivery of levodopa to the brain and pharmacodynamic factors influencing dopamine receptor function
are postulated causes for the motor fluctuations C41.
The observation that patients experiencing on-off phenomena can be maintained reasonably mobile and
ambulant during continuous intravenous infusion of
levodopa suggests that pharmacokinetic factors, particularly fluctuations in plasma levodopa levels, are important in the genesis of on-off motor fluctuations f l l ,
13, 161. Although intravenous infusion of levodopa
attenuates motor fluctuations, this mode of administration is not feasible for long-term therapy.
Based on a hypothesis that erratic gastric emptying
of orally administered levodopa is at least partly responsible for fluctuations in plasma levels of the amino
acid, and because of the potential feasibility of direct
and chronic duodenal delivery of levodopa, we investigated the efficacy of nasoduodenal administration of
levodopa in 3 patients with parkinsonism who had severe on-off fluctuations that were resistant to adjustments in the oral administration of levodopa or the
addition of dopamine agonists [ S , 6}.
Case Reports
Patient I
A 66-year-old man had a 7-year history of idiopathic Parkinson’s disease, manifested by resting tremor, rigidity, bradykinesia, and postural instability. He had developed progressively worsening immobility, finally characterized by random
oscillations of motor function. H e required multiple ad justments of his levodopa (administered as Sinemet {carbidopalevodopa}) regimen, and trials of other antiparkinsonian
medications, including amantadine, bromocriptine, and pergolide. However, motor fluctuations persisted. Average daily
mobile “on” time was 2 hours according to the patient’s daily
diary. At the time of study, the patient was receiving
Sinemet 25/250 every 2% hours ( 5 AM to 10:30 PM);amantadine, 100 mg twice daily; and amitriptyline, 30 mg every
night.
The patient was hospitalized, and a Dobhoff nasoduodenal
tube was passed with the distal end localized radiographically
to the proximal duodenum. During three 10- to 12-hour
observation periods, levodopa was administered as follows:
(1) orally in the form of Sinemet tablets (25/250 every 2%
hours, 5 AM to 10:30PM); (2) by intermittent duodenal bolus
of the same dose of Sinemet dissolved in ascorbic acid; and
( 3 ) by continuous duodenal infusion of levodopa (7 AM to 11
PM daily). For continuous infusion, levodopa was dissolved
in sterile water as a 2% ascorbic acid solution and the infusion rate was regulated by a mechanical pump. The levodopa
infusion rate was adjusted over 3 days to achieve optimal
parkinsonian mobility. Carbidopa (50 mg four times daily)
was given orally during the infusion. During each observation period, motor functions were rated hourly by the patient
on a - 5 to 0 scale for parkinsonism (0 = normal mobility;
- 5 = severe parkinsonism), and a 0 to + 5 scale for severity
of dyskinesia (0 = none; + 5 = most severe). Times were
DYSKlNESlA
ORAL SINEMET
SEVERITY
1
+2
PARKINSONISM
SEVERITY
MEAN
MOBILITY
( t s.d.)
1
-;1
‘a-e-e-a
4
4
I
/
ae
-
4
4
4
-2.4
2
2.4
4
A
CONTINUOUS DUODENAL INFUSION
1
1
’ . ,*
B
INTERMITTENT DUODENAL BOLUS
1
1
1
1
1
5
6
7
8
9
C
AM
1
1
10 I I
l
1
1
1
I2
1
2
3 4
-I
1
1
1
5 6
PM
REPRESENTS INDEPENDENCE IN PERFORMING
ACTIVITIES OF DAILY LIVING
Ratings of parkinsonism (- 3 to 0: 0 = normal mobility, - 5
= severe parkinsonism) and dyskinesia (0 to + 5: 0 = none,
-I-5 = most severe) for Patient 1 during three modes of levodopa
administration: (A)oral Sinemet; (B) continuous duodenal infusion; and (C) intermittent duodenal bolus. Awmbeads (A and
C) indicate times of levodopa administration and solid bar (B)
indicates duration of levodopa infusion.
also noted during the observation period when the patient
could independently perform daily living activities.
Continuous duodenal infusion of levodopa at a rate of 96
mg per hour (77% of baseline daily oral dose) produced
optimal mobility. This method of administration (Figure, B)
resulted in improved mobility (p < 0.001 by Student’s t test
for paired data) ( - 0.4
1.8, mean 5 SD) compared with
oral Sinemet administration ( - 2.4 ? 2.4; Figure, A). Intermittent duodenal bolus administration (Figure, C) also resulted in improved mobility ( - 1.1 ? 1.1) compared with
the oral route, but this difference was less pronounced than
that with continuous infusion and did not attain statistical
significance (p < 0.06). Subsequent treatment for one year
with intermittent duodenal bolus administration (chosen by
the patient to avoid the inconvenience associated with the
use of an infusion pump) has been well-tolerated and has
resulted in an increase in average daily “on” time from 2 to
*
12 hours and has reduced motor fluctuations. On three occasions, transient worsening of parkinsonian mobility corresponded to times when the distal end of the nasoduodenal
tube slipped back into the stomach.
Patient 2
A 75-year-old man had a 17-year history of idiopathic Parkinson’s disease, characterized by progressive decline in mobility and eventually random oscillations in motor function.
These severe on-off effects were resistant to multiple adjustments of his levodopa (administered as Sinemet) regimen,
and to trials of other antiparkinsonian medications, including
benztropine, amantadine, bromocriptine, and pergolide. At
the time of evaluation, he was experiencing only 1 to 2 hours
of “on” time daily and medications included Sinemet 5/50
every 3 hours (9 AM to 9 PM) and amantadine 100 mg rwice
daily.
The patient was hospitalized due to severe parkinsonian
immobility in association with anarthria and dysphagia (including difficulty swallowing medications and recurrent aspiration). A nasoduodenal tube was passed and the distal end
was localized radiographically to the proximal duodenum.
One gram of levodopa was dissolved in 1 liter of a 2%
ascorbic acid solution and administered by continuous
duodenal infusion (7 AM to 11 PM) regulated by a mechanical
pump. Carbidopa (50 mg four times daily) was given orally
Brief Communication: Kurlan et al: Duodenal Delivery of Levodopa
263
during the infusion. The levodopa infusion rate was adjusted
over 7 days to achieve optimal parkinsonian mobility. At an
infusion rate of 10 mg per hour (64% of daily oral levodopa
dose), the patient became mobile, independently ambulatory, and conversant. There was marked improvement in
swallowing function, and motor fluctuations virtually disappeared. O n two occasions, the beneficial effect of levodopa
infusion was lost when the distal end of the tube transiently
slipped back into the stomach. The excellent level of motor
function was maintained for 3 weeks. However, the patient
then developed visual and auditory hallucinations, which persisted despite steady reduction of the infusion rate to 1 mg
per hour. Levodopa infusion was discontinued and the patient returned to a state of severe parkinsonism with dysphagia and anarthria. Recurrent aspiration pneumonia supervened. Reinstitution of levodopa duodenal infusion was not
tolerated because of persistent hallucinations. Acceptable
parkinsonian mobility was achieved with the readministration of small doses of Sinemet orally.
Patient 3
A 40-year-old woman had a 6-year history of parkinsonism
complicated by end-of-dose deterioration and prominent
peak-dose, end-of-dose, and early morning dystonia. Antiparkinsonian drug therapy was limited by a narrow thera:
peutic window-low drug dosage resulted in unacceptable
parkinsonian mobility and higher doses caused disabling
dystonia. Therapeutic trials of anticholinergic medications,
amantadine, bromocriptine, and pergolide produced only
limited benefit. At the time of evaluation, her medications
included Sinemet 25/100, 1% tablets alternating with 1 tablet
every 3 hours (7 AM to 10 PM).
Sinemet was discontinued and carbidopa (50 mg three
times daily) was administered orally. A nasoduodenal tube
was placed and the distal end was localized radiographically
to the proximal duodenum. A solution of levodopa, 1 gm in
1 liter of sterile water as a 2% ascorbic acid solution, was
infused through the tube (7
to 11 PM) using a mechanical
pump. Levodopa infusion rate was adjusted over 10 days to
achieve optimal parkinsonian mobility. At an infusion rate of
52 mg per hour (111% of daily oral levodopa dose), she was
able to rise from a chair, walk, feed herself, and perform
most daily activities independently. She estimated that her
mobility had improved by 50% over her pre-infusion status.
Dystonic dyskinesias persisted but were of substantially
lower severity, and motor fluctuations virtually disappeared.
O n three occasions, the beneficial effect of levodopa infusion
was lost when the distal end of the tube transiently slipped
back into the stomach. Continuous (7 AM to 11 PM) infusion
of levodopa has been maintained for 2 months on an outpatient basis using an ambulatory mechanical (Cormed)
minipump, resulting in sustained therapeutic benefit.
Discussion
The beneficial effects of continuous and intermittent
direct duodenal administration of levodopa suggest
that erratic gastric emptying of the orally administered
264 Annals of Neurology Vol 20 No 2
August 1986
amino acid plays an important role in the pathogenesis
of on-off fluctuations. Direct duodenal delivery of
levodopa minimizes this difficulty and may be suitable
for long-term therapy.
The stomach has a very limited capacity to absorb
orally administered levodopa but is able to decarboxylate this amino acid [lo, 143. Most levodopa absorption appears to take place in the proximal small intestine. Thus, the major role of the stomach is that of a
valve, controlling the delivery of an ingested levodopa
bolus to intestinal absorptive sites [lo]. This notion
is supported by the observation that absorption of
levodopa is extremely rapid in gastrectomized patients
or after duodenal instillation [1, 2, 143. Gastric emptying is influenced by gastric acidity and, as might be
predicted, an inverse relationship between gastric acidity and the time to peak plasma Concentration of
levodopa, as well as its magnitude, has been shown [2,
10, 12).
Extremely slow gastric emptying resulting from excessive gastric acidity has been demonstrated to reduce
levodopa absorption and therapeutic effect in one parkinsonian patient [ls}. Administration of antacids enhanced gastric emptying, increased levodopa absorption, and augmented the therapeutic effect in this
subject. However, chronic administration of an antacid
with levodopa to 3 randomly selected parkinsonian patients failed to alter the therapeutically effective dose
[73. The commonly observed multiple plasma peaks of
levodopa after a single oral dose have been attributed
to erratic gastric emptying 13, 173. Meals may delay
the appearance of the drug in plasma, possibly reflecting delayed gastric emptying caused by the food [l, 9,
111.
Thus, clinical and experimental evidence indicates
that gastric emptying importantly influences levodopa
absorption. Erratic gastric emptying may therefore
contribute to unsteady levodopa absorption and fluctuating plasma levels. These gastrointestinal pharmacokinetic factors may be of prime importance in the
development of on-off phenomena. Our observations
indicate that the difficulty of erratic gastric emptying
can be overcome by direct duodenal administration oj
the drug. This mode of delivery ameliorates motoi
fluctuations and is suitable for chronic therapy, particu.
larly with the advent of improved ambulatory infusion.
pump technology. The development of persistent hal
lucinations by one of our patients during continuou!
infusion of even very low doses of levodopa suggest!
that this mode of administration may facilitate passagt
of the amino acid into the central nervous system
Further studies are under way to correlate clinical rat
ings with circulating levels of levodopa and its 0
methylated metabolite, and to clarify the pharmaco
kinetic factors of duodenal delivery.
This work was supported by a United Parkinson Foundation fellowship (Dr Rubin) and USPHS grant RR00044 (University of Rochester Clinical Research Center).
We thank Mrs Ruth Nobel for secretarial assistance.
References
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Reduced Phospholipase
D Activity in Brain Tissue
Samples from Alzheimer’s
Disease Patients
Julian N. Kanfer, PhD, Hiroshi Hattori, MD, PhD,
and Danka Orihel. BSc
Biochemical examinations of brain tissue samples obtained from patients with Alzheimer’s disease have revealed a decreased quantity of the neurotransmitter
acetylcholine and reduced activity of choline acetyltransferase (ChAT), the enzyme responsible for acetylcholine formation. It has been suggested that the
choline moiety of lecithin, a substitute ubiquitously
present in membranes of mammalian cells, could be
mobilized for acetylcholine formation. The activity of
phospholipase D, an enzyme which releases choline directly from lecithin, was measured in homogenates of
Alzheimer brain tissue and found to be reduced by 63%.
ChAT activity was reduced by 58% and 5‘-nucleotidase
activity was reduced by 2770 in these homogenates.
Kanfer J N , Hattori H, Orihel D :
Reduced phospholipase D activity in brain
tissue samples from Alzheimer’s disease patients.
Ann Neurol 20~265-267, 1986
Alzheimer’s disease has been the subject of symposiums, a text, and review articles 12, 8, 101. A characteristic postmortem morphological observation is the
selective loss of cholinergic neuronal cells in the basal
forebrain, particularly in the nucleus basalis of Meynert. Immunohistochemical results have correlated
with this loss a decreased number of choline acetyltransferase (ChAT)-staining neurons in brain tissue
from the basal forebrain of patients with senile dementia 191. Therapeutic approaches, based upon the “cholinergic hypothesis” that evolved from such hndings
[33, were formulated and featured nutritional supplementation with free choline o r choline-containing
compounds. It was proposed that the lecithin present
in the neuronal cell membranes could be a repository
for choline destined to become acetylcholine, and this
process has been termed auto-cannibulism 131.
From the Department of Biochemlstry, Faculty of Medicine, University of Manitoba, 770 Bannatyne Ave, Winnipeg, Manitoba R3E
OW3, Canada.
Received Sept 9, 1985, and in revised form Nov 5 and Dec 10.
Accepted for publication Dec 20, 1985.
Address reprint requests to Dr Kanfer.
265
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