Camilla Flintermann wrote:
<<We've been trying to get a med routine that will help Peter with the
awful lethargy he experiences at many times through the day. About 6
weeks
ago the neuro put him on 6XSin>CR 50/200 at 4 hour intervals around the
clock--no improvement. Today I went armed with info from this list re:
CARBIDOPA, and when I suggested that 300mg x day was too much, he
agreed, said "that's what I might have said myself" (but of course he
DIDn't say it first) and agreed to move P. off the CRs and try 25/250mg
Sinemet instead. He
suggested starting with 4 x day, but said we could go to 5 or 6 if
needed,
and still be at 1/2 the carbidopa P. gets now. To my question about
toxicity, a point Alan Bonander made on the list, he shrugged, and said
there's no evidence of that, it's just that you don't*need*more than
70-100mg carbidopa. This leads me to ask if anyone has evidence to cite
about toxicity? Or is it one of those "possible" things we so often
encounter with PD?>>
Brian Collins sent Pat Martin's words about the non-specificity of
carbidopa, so I will not repeat that.
I will include portions of the following:
Dietary Factors in the Management of Parkinson's Disease
P.A. Kempster, M.D., M.R.C.P. (U.K.), F.R.A.C.P. and M. L. Wahlqvist,
M.D., F.R.A.C.P.
Dr. Kempster is with the Departments of Neurosciences and Medicine and
Dr. Wahlqvist is with the Department of Medicine. Monash Medical
Centre, 246 Clayton Rd., Clayton 3168. Melbourne. Australia.
ABSTRACT
Oral administration of L-dopa is currently the most effective way to
treat the cerebral dopamine deficiency which causes Parkinson's disease.
Unfortunately, many patients with advanced Parkinson's disease develop
an unstable pattern of response to L-dopa because of fluctuating
delivery of the drug to the brain. Diet contributes to this problem
through Its adverse effects on L-dopa pharmacokinetics. This article
reviews dietary strategies to improve responsiveness to pharmaceutical
L-dopa treatment and the potential use of food as a source of L-dopa.
Nutritional factors concerning weight loss and energy balance in
Parkinson's disease are also discussed. A set of dietary guidelines is
developed to assist clinical nutritionists and neurologists in the
practical management of patients with Parkinson's disease. Nutrition
Reviews 1994;52,2:51-58 Feb 1994
L-Dopa medication is now usually initiated in patients with relatively
mild Parkinson's disease early in the course of the illness. Modern
treatment combines L-dopa with a peripheral decarboxylase enzyme
inhibitor (carbidopa or benserazide) to minimize conversion of L-dopa to
dopamine outside the nervous system. In most cases, motor symptoms
improve and a stable and satisfactory response continues for the next
few years. With further disease progression, many patients begin to
experience fluctuation of response to L-dopa, and drug-induced
dyskinetic involuntary movements may then accompany the beneficial
effects of the medication. Significant motor fluctuations develop at a
rate of about l0% per treatment year.[4] In their most severe form,
motor fluctuations produce, the "on-off" syndrome.[5] Patients with
this affliction swing between severe Parkinsonian disability ("off'
phases) and relative improvement of motor fluctuation which restores
mobility at the expense of involuntary movements ("on" phases).
Capricious and abrupt fluctuation between these states occurs many times
a day. The fact that patients cannot predict when sudden loss of
independent mobility will occur is in itself a major cause of disability
in this syndrome.
The pharmacokinetic properties of L-dopa lead to fluctuating blood
levels, generating fluctuation of motor function in susceptible
patients.[6] The drug has a relatively short half-life because of
enzymic catabolism; and dietary intake is apt to interfere with its
absorption and transport within the body. Fluctuating delivery of L-dopa
to the brain does not seem to matter early in the disease course.
However, disease progression brings increasing dependence on
pharmacological dopamine receptor stimulation. Severe motor fluctuations
are generally seen in patients who retain a capacity to respond well to
L-dopa but have lost most of their endogenous dopamine production
because of nigral cell loss. A precipitous decline in motor functions
thus occurs each time that the supply of exogenous L-dopa to the brain
lapses.
Table 1. Dietary Factors Which Affect Clinical Response to L-Dopa
Medication
1. Timing of L-dopa doses in relation to mealtime.
2. Effects of food on gastric emptying
Energy content of food
Meal size
Food viscosity
3. Competition between dietary neutral amino acids and L-dopa for
absorption across the intestinal mucosa.
4. Competition between circulating neutral amino acids and L-dopa for
active transport across the blood-brain barrier.
DIETARY INFLUENCES ON L-DOPA PHARMOCOKINETICS
L-Dopa is normally present as an intermediate metabolite in neurons
which produce catecholamine neurotransmitters (dopamine, noradrenaline,
adrenaline). It is synthesized by the enzyme tyrosine hydroxylase from
the diet-derived aromatic amino acid tyrosine. Brain tyrosine
hydroxylase is confined to dopaminergic and noradrenergic neurons, has a
high affinity for its substrate tyrosine, and its activity is regulated
by the rate of neuronal firing.[9,10]
Administration of tyrosine to Parkinsonian patients may increase
dopamine synthesis and turnover in the central nervous system,[11] but
there is no evidence of any clinical benefit from treatment with
tyrosine. Phenylalanine is an indirect amino acid precursor of L-dopa
but has no clinical effect on Parkinsonism.[12] A normal diet contains
little L-dopa.[13] and the small amount of circulating L-dopa in normal
subjects probably emanates from synthetic activity in peripheral
sympathetic neurons and the adrenal medulla.[14]
To exert its action In Parkinson's disease, L-dopa must he absorbed from
the gastrointestinal tract into the bloodstream, cross the blood-brain
barrier, and then be enzymatically converted to dopamine within the
brain to interact with striatal dopamine receptors. Intake of food,
particularly protein, can interfere with this process at a number of
levels. Single oral doses of L-dopa, when administered in the fasting
state, produce efficient and reliable absorption of L-dopa, which
corresponds to predictable and relatively prolonged motor responses even
in patients with the most erratic pattern of response to their usual
oral L-dopa medication.[15]
Patients are often advised to take L-dopa doses with meals. By reducing
L-dopa absorption, food may reduce side effects such as nausea on first
exposure to medication containing L-dopa. However once motor
fluctuations have developed after prolonged treatment, food is usually a
hindrance to the bioavailability and clinical effectiveness of L-dopa.
L-Dopa is optimally absorbed from the duodenum and proximal jejunum.[16]
The drug is not absorbed across gastric mucosa,[17] but oral doses are
dependent on gastric emptying for access to absorption sites. The rate
of gastric emptying is chiefly determined by the energy content of food
and is inversely proportional to the energy density of meal.[18] Thus
fat will retard gastric emptying to greater degree than either protein
or carbohydrate. Low gastric acidity slows emptying [19] although
routine administration of antacids to Parkinsonian patients does not
improve L-dopa absorption.[20] Some types of dietary fiber increase
food viscosity and slow gastric emptying.[21] The gastric mucosa
contains the enzyme dopa decarboxylase,[22] which will catalyze unwanted
conversion of L-dopa to dopamine, reducing the amount of L-dopa
available for subsequent absorption from doses affected by delayed
gastric emptying.
When L-dopa is administered by naso-duodenal tube[23] or to subjects who
have previously had a gastrectomy,[19] absorption is very rapid and
efficient. Effects on gastric emptying are probably largely responsible
for the observation that when L-dopa is given with food, the rise in
plasma concentration is reduced, delayed and unpredictable as compared
with fasting.[24,25]
On reaching the proximal small gut, L-dopa crosses the mucosal barrier
by a stereospecific, saturable active transport mechanism shared by
large neutral amino acids such as phenylalanine, tyrosine, tryptophan,
leucine, isoleucine, valine, methionine, and histidine.[26] Dietary
protein can thus lead to competition for these active carrier sites.
Once L-dopa molecules have reached the bloodstream, access to the brain
is dependent on similar active amino acid transport across the
blood-brain barrier for which it must compete with other circulating
neutral amino acids.[27]
Intravenous infusion of L-dopa at a constant rate can produce stable and
sustained motor responses in patients with motor fluctuations. When oral
protein or neutral amino acid loads are then administered, a transient
loss of response occurs without change in blood L-dopa concentration,
indicating a block to L-dopa passage into the brain through competition
for transport across the blood-brain barrier.[24] Constant rate
intraduodenal infusion also produces efficient L-dopa absorption, stable
L-dopa blood level, and sustained clinical responses in fasting
patients. With oral administration of protein, the relative importance
of competition by dietary neutral amino acids at gut and blood-brain
barrier levels can be compared. Oral protein causes a loss of clinical
response to L-dopa without affecting blood concentration: this indicates
that the major site of interference between L-dopa and amino acid active
transport is at the blood-brain barrier.[28] Experimental data regarding
the equilibrium constant for active transport of large neutral amino
acids also agree with this observation. In gut, as in most tissues, the
equilibrium constant is considerably higher than physiological
concentrations of neutral amino acids. However, the constant for brain
capillary endothelial cells (which form the physiological
blood-brain-barrier) is about 10 times less than for other tissues and
approaches the sum of postprandial plasma concentrations of large
neutral amino acids.[29]
Unpredictability is a major feature of severe motor fluctuations.
Although patients experience the fluctuations every day, the timing of
dramatic changes in motor disability and the amount of "on" and "off"
time per day are never the same despite constant pharmacological
treatment. Erratic L-dopa absorption due to the influence of food on
gastric emptying[30] and the dissociation between L-dopa plasma
concentration and clinical effect because of dietary neutral amino acids
in the bloodstream[31] appear to be the chief factors generating the
unpredictable element of motor fluctuations.
However, the most effective dietary strategy involves redistribution of
protein intake.[31] This requires protein to be virtually excluded in
food taken during the day (protein content restricted to 7 g) with daily
protein requirement being made up in a high-protein evening meal. Carter
et al compared various diets in a group of fluctuating patients on
standard oral L-dopa medication. While taking an average American amount
of protein in their diet, these patients were "on" for 51% of the
waking day. When protein intake was reduced to the RDA level, "on" time
increased to 61% and when a protein redistribution diet was taken,
patients remained "on" for 71% of the time.[35] The protein
redistribution diet requires considerable reorganization of mealtimes,
and patients have to accept a period of loss of response to medication
following the higher-protein evening meal. Nevertheless, with
appropriate dietary guidance and encouragement, the majority of patients
are able to comply with the diet. About 60% of patients report
improvement in control of motor symptoms and a more stable response to
L-dopa, usually within a few days.[34] The diet offers no benefit to
patients who do not fluctuate because of poor responsiveness to
L-dopa.[34]
Long-term experience with the protein redistribution diet suggests that
70% of patients who gain an initial advantage will use the diet for 12
months or more.[37] A study of the nutritional status in patients
restricting daytime protein intake for 2 months showed that significant
reduction in the intake of protein, calcium, phosphorus, iron,
riboflavin, and niacin occurred.[38] However, only calcium intake fell
to below the RDA level, probably because of a restriction on the intake
of dairy products. Body weight and serum prealbumin concentration did
not change significantly. Although dietary protein redistribution is an
effective long-term treatment in some patients, careful monitoring of
nutrition is required. This is of particular importance when the usual
diet is marginally adequate and when patients are at risk for
osteoporosis.
Manipulation of dietary components other than protein has been studied
less extensively. Carbohydrate loads, by stimulating insulin secretion,
reduce circulating amino acid levels.[39] This may be the explanation
for the observation that the effectiveness of oral L-dopa doses is
enhanced by glucose loading.[40] Berry et al administered balanced
carbohydrate:protein (ratio = 5) meals to Parkinsonian patients and
found that plasma neutral amino acid levels did not change.[41] They
suggested that the effect of carbohydrate in lowering amino acid
concentration could cancel out the rise following a moderate protein
load and that a balanced dietary intake may be as effective as protein
restriction/redistribution.
Limiting or redistributing protein intake may minimize competitive
inhibition of transmembrane passage of L-dopa into the brain but may not
be the best way to influence other forms of dietary interference with
the action of L-dopa, particularly the effects of food on gastric
emptying. Redistribution of the dietary energy content or adjustment of
the fiber-type and viscosity of meals may allow more efficient access of
L-dopa medication to absorption sites. These forms of dietary
manipulation have not been systematically evaluated in Parkinson's
disease. Meal size will also affect the time taken for gastric emptying.
Small snacks taken with L-dopa medication do not significantly interfere
with the clinical response to the drug.[42] However, dividing daily
dietary intake into multiple small feedings rather than three standard
meals does not improve the effectiveness of treatment.[33]
selected refs:
6. Shoulson I, Glaubiger GA, Chase TN. On-off response: clinical
and biochemical correlations during oral and intravenous levodopa
administration In Parkinsonian patients. Neurology 1975;25:1144-8
15. Kempster PA, Frankel JP, Bovingdon M, Webster R, Lees AJ, Stern
GM. Levodopa peripheral pharmacokinetics and duration of motor response
in Parkinson's disease. J Neurol Neurosurg Psychiatry 1989; 52:718-23
17. Bianchine JR, Calimlim LR, Morgan JP, Dujovne CA, Lasagna L.
Metabolism and absorption of L-3,4-dihydroxyphenylalanine in patients
with Parkinson's disease. Ann NY Acad Sci 1971;179:126-40
18. Hunt JN, Stubbs DF. The volume and energy content of meals as
determinants of gastric emptying. J Physiol 1975;245:209-25
19. Riviera-Calimlim L, Dujovne CA, Morgan JP, Lasagna L, Bianchine
JR. Absorption and metabolism of L-dopa by the human stomach. Eur J Clin
Invest 1971;1:313-20
20. Leon AS, Spiegel HE. The effect of antacid administration on the
absorption and metabolism of levodopa. J Clin Pharmacol 1972;12:263-7
21. Schwartz SE, Levine RA, Singh A, Scheidecker JR, Track NS.
Sustained pectin ingestion delays gastric emptying. Gastroenterology
1982;83:812-7
22. Rivera-Calimlim LR, Morgan JP,,Dujovne CA, Bianchine JR, Lasagne
L. L-3,4-Dihydroxyphenylalanine metabolism by the gut in vitro. Biochem
Pharmacol 1971;20:3051-7
24. Nutt JG, Woodward WR, Hammerstad JP, Carter JH, Anderson JL.
"On-off" phenomenon in Parkinson's disease: relationship to levo-dopa
absorption and transport. N EngI J Med 1984;310:483-8
25. Baruzzl A, Contin M, Riva R, et al. Influence of meal Ingestion
time on pharmacokinetics of orally administered levo-dopa In
Parkinsonian patients. Clin Neuropharmacol 1987;10:527-37
26. Wade DN, Mearick PT, Morris JL. Active transport of L-dopa in
the intestine. Nature 1973;242:463-5
27. Wade LA, Katzman R. Synthetic amino acids and the nature of
L-dopa transport at the blood-brain barrier. J Neurochem 1975;25:837-42
28. Frankel JP, Kempster PA, Bovingdon M, Webster R, Lees AJ, Stern
GM. The effects of oral protein on the absorption of intraduodenal
tevodopa and motor performance. J Neurol Neurosurg Psychiatry
1989;52:1063-7
29. Pardridge WN. Kinetics of competitive inhibition of neutral
amino acid transport across the blood-brain batrier. J Neurochem
1977;28:103-8
30. Kurlan R, Rothfield KP, Woodward WR, et al. Erratic gastric
emptying of levodopa may cause "random" fluctuations of Parkinsonian
mobility. Neurology 1988;38:419-21
31. Pincus JH, Barry KM. Plasma levels of amino acids correlate with
motor fluctuations In Parkinsonism. Arch Neurol 1987;44:10O-9
32. Mena I, Cotzias GC. Protein intake and treatment of Parkinson's
disease. N EngI J Med 1975;292:181-4
33. Juncos JL, Fabbrini G, Mouradian MM, Serrati C, Chase TN.
Dietary Influences on anti-Parkinsonian response to l-dopa. Arch Neurol
1987;44:1003-5
34. Riley D, Lang AE. Practical application of a low protein diet
for Parkinson's disease. Neurology 1988;38:1026-3
43. Guggenheim M. Dioxphenylalanine, a new amino acid from Vicia
faba. Z Physiol Chem 1913;88:276-84
44. Spengos M Vassilopoulos D. Improvement of Parkinson's disease
after Vicia faba consumption. Book of abstracts, 9th International
Symposium on Parkinson's disease 1988:46
45. Rabey JM, Vered Y, Shabtai H, Graff E, Korczyn AD. Improvement
of Parkinsonian features correlate with high plasma levodopa values
after broad bean (Vicia faba) consumption. J Neurol Neurosurg Psychiatry
1992;55:725-7
46. Kempster PA, Bogetic Z, Secombe JW, Martin HD, Balazs NDH,
Wahlqvist ML. Motor effects of broad beans (Vicia faba) in Parkinson's
disease: single dose studies. Asia Pac J Clin Nutr 1993;2:85-89
48. Andrews RS, Pridham JB. Structure of a dopa glucoside from Vicia
faba. Nature 1965;205:1213-4
49. Miller ER. Dihydroxyphenylalanine, a constituent the velvet
bean. J Biol Chem 1920;44:481-6
50. Damodaran M, Ramaswamy R. Isolation of L-3,4-
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If anyone can get me refs: 6, 15, 17,19,24,25,29,31, and/or 45, I would
very much like to read them. If any are available on the net, I would
appreciate a clue to locate.
apology for being so long.
--
ron 1936, dz PD 1984 Ridgecrest, California
Ronald F. Vetter <[log in to unmask]>
http://www.ridgecrest.ca.us/~rfvetter
