L-Dopa

Brand Names: Dopar, Larodopar, Sinemet

Clinical Names: L-Dopa, Levodopa

Summary

generic name: Levodopa

trade name: L-Dopa, Dopar®, Larodopar®, Sinemet®

note: Sinemet®, Levodopa-carbidopa, is a combination of two drugs, levodopa and carbidopa.

type of drug: Sympathetic stimulant.

mechanism: Parkinson's disease is believed to be related to low levels of dopamine in certain parts of the brain. When levodopa is taken orally, it crosses through the "blood-brain barrier." Once it crosses, it is converted to dopamine. The resulting increase in brain dopamine concentrations is believed to improve nerve conduction and assist the movement disorders in Parkinson's disease. Carbidopa does not cross the blood-brain barrier. Carbidopa is added to the levodopa to prevent the breakdown of levodopa before it crosses into the brain. The addition of carbidopa allows lower doses of levodopa to be used. This reduces the risk of side effects from levodopa such as nausea and vomiting.

used to treat: management of symptoms of Parkinson's disease.

overview of interactions:
• nutrient affecting drug performance: Vitamin B6

• nutrients affecting drug performance: Tyrosine and Phenylalanine

• reduced drug absorption, bioavailability or activity: High Levels of Dietary Protein



Interactions

nutrient affecting drug performance: Vitamin B6

• mechanism: Levodopa is a vitamin B6 antagonist.

• nutritional concerns: Supplementation of Vitamin B6 at different levels can produce significantly different effects.
Vitamin B6 deficiency can be avoided by supplementing at low levels of 5-10 mg per day or less. While larger doses of B6 should be avoided as they allow L-dopa to be metabolized to dopamine and can inactivate the drug. Note, however, that this contraindication does not hold for patients using Sinemet as the carbidopa component inhibits the effect of vitamin B6 on the dopa pathway. Thus, patients using Sinemet will not experience any adverse interaction from supplementing with vitamin B6.
(Trovato, A, et al. Am Family Phys 1991;44:1651-1658; Long, JW. 1992.)

nutrients affecting drug performance: Tyrosine and Phenylalanine

• mechanism: L-Tyrosine is a semi-essential amino acid that converts to L-Dopa. Phenylalanine is a precursor of L-tyrosine.

• nutritional concerns: Supplementation of L-tyrosine, or its precursor phenylalanine, may serve as a valuable adjunctive therapy in the treatment of Parkinson's disease or similar conditions. However, such supplementation by individuals using Levodopa may raise levels of L-Dopa to undesirably high levels. Anyone taking Levodopa should consult the prescribing physician and/or a nutritionally-oriented doctor regarding the issue of supplementation with either of these amino acids. Nutritionally-oriented physicians will want to closely monitor the L-Dopa levels of any individual using these substances together.

reduced drug absorption, bioavailability or activity: High Levels of Dietary Protein

• nutritional concern: A variety of researchers have suggested that dietary protein makes levodopa less available to the brain. It is known that certain large neutral amino acids (LNAA) compete with levodopa for a transport mechanism across the blood brain barrier. There have also been a small number of case reports of patients who feel that they move less well after a high protein rather than a low protein meal.

• mechanism: The transport molecule is a saturable, facilitated transport mechanism. Levodopa and the amino acids compete with one another for transport across the barrier by this transport molecule. Consequently, the ratio of levodopa to LNAA is the same in the blood and the interstitial fluid of brain. As Parkinsons progresses, dopamine stores in the brain become greatly reduced to the point where patients may become totally dependent on the minute-to-minute availability of dopamine from levodopa in the brain. As a result they are also dependent on the plasma ratio of levodopa to LNAA. An increase in the plasma ratio of levodopa to LNAA might increase dopamine in brain.

• nutritional support: It might be possible to achieve an increase in the plasma ratio of levodopa to LNAA by one of the following methods:
* Increase in levodopa] in plasma by an increase in dosage; however, this has not been found to be effective; or
* Decrease in LNAA in plasma by a very low protein, high carbohydrate diet.
(Carter JH et al. Neurology. 1989;39:552-556; Eriksson T et al. Neurology 1988;38:1245-1248; Juncos JL et al. Arch Neuro. 1987;44:1003-1005; Kurlan R. Arch Neurol. 1987;4:1119-1121; Mena I, Cotzias GC. NEJM. 1975;292:181-184; Nutt JG et al. NEJM. 1984;310:483-488; Pincus JH, Barry KM. Arch Neurol. 1987;44:270-272; Pincus JH and Barry KM. Arch Neurol. 1987;44:1006-1009; Pincus JH, Barry KM. Yale J Biol Med. 1987;60:133-137; Pincus JH, Barry KM. Neurology. 1988;38:481-483; Riley D and Lang AE. Neurology. 1988;38:1026-1031; Wurtman R, et al. NEJM. 1988;319:1288-1289; Bracco F, et al. Eur Neurol. 1991;31(2):68-71.)


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Do not rely solely on the information in this article.

The information presented in Interactions is for informational and educational purposes only. It is based on scientific studies (human, animal, or in vitro), clinical experience, case reports, and/or traditional usage with sources as cited in each topic. The results reported may not necessarily occur in all individuals and different individuals with the same medical conditions with the same symptoms will often require differing treatments. For many of the conditions discussed, treatment with conventional medical therapies, including prescription drugs or over-the-counter medications, is also available. Consult your physician, an appropriately trained healthcare practitioner, and/or pharmacist for any health concern or medical problem before using any herbal products or nutritional supplements or before making any changes in prescribed medications and/or before attempting to independently treat a medical condition using supplements, herbs, remedies, or other forms of self-care.



References

Bracco F, Malesani R, Saladini M, Battistin L. Protein redistribution diet and antiparkinsonian response to levodopa. Eur Neurol. 1991;31(2):68-71.
Abstract: Sixteen parkinsonian patients with daily fluctuations in the clinical response to levodopa have been placed on a redistribution protein diet. The diet was virtually protein-free until the evening meal and then unrestricted until bedtime. While on the redistribution protein diet, a group of patients (5 out of 16) had a clear and significant benefit from dietary therapy showing a definite reduction of diurnal motor performance fluctuations. In addition, all patients tended to show an improvement and a more constant response to levodopa treatment. A trial of redistribution protein diet appears a simple, reasonable, worthwhile approach to PD patients who begin to experience oscillating clinical response to levodopa treatment.

Carter JH, Nutt JG, Woodward WR, Hatcher LF, Trotman TL. Amount and distribution of dietary protein affects clinical response to levodopa in Parkinson's disease. Neurology. 1989 Apr;39(4):552-556.
Abstract: Reducing dietary protein improves the effectiveness of levodopa (LD) but the most effective distribution of a low-protein diet (0.8 g/kg) is unclear. We compared a 1.6 g/kg protein diet, a 0.8 g/kg diet with protein evenly distributed between meals, and a 0.8 g/kg diet with protein restricted to the evening meal in 5 parkinsonian patients with motor fluctuations. We monitored clinical response, plasma LD, and plasma large amino acids (LNAAs) hourly throughout the day. Mean "on" times were 51% (1.6 g/kg diet), 67% (0.8 g/kg evenly distributed), and 77% (0.8 g/kg restricted). Hourly averages of plasma LD did not differ between the diets. The mean plasma LNAAs were 732 nmol/ml (1.6 g/kg diet), 640 (0.8 g/kg distributed), and 542 (0.8 g/kg restricted), and the diurnal pattern reflected the distribution of protein intake. In conclusion, the amount and distribution of dietary protein affect clinical response to LD. These effects are not related to LD absorption but are explained by the variation in plasma LNAAs.

Eriksson T, Granerus AK, Linde A, Carlsson A. "On-off" phenomenon in Parkinson's disease. Neurology 1988;38:1245-1248.
Abstract: Administration of a low-protein diet to parkinsonian patients with "on-off" syndromes consistently increased the total daily time of "on" states when compared with a high-protein diet. The clinical effect of the low-protein diet may be due to a marked decrease in the plasma concentration of large neutral amino acids that compete with L-dopa for carrier-mediated transport into the brain.

Haavik J. L-DOPA is a substrate for tyrosine hydroxylase. J Neurochem 1997 Oct;69(4):1720-1728.
Abstract: In the presence of thiols, tyrosine hydroxylase (TH) oxidizes L-dihydroxyphenylalanine (L-DOPA) with a specific activity of up to 140 nmol min(-1) mg(-1) at 37 degrees C and pH 7.0, which is approximately 12-50% of its TH activity under similar experimental conditions. Using assay conditions that are optimal for measuring TH activity, the specific DOPA oxidase activity of human TH is similar to that of mushroom tyrosinase, but the two enzymes are clearly different in terms of substrate specificities, cofactor dependencies, and selectivity with respect to the effects of metal chelators and other inhibitors. In the presence of an excess of dithiothreitol, 2-mercaptoethanol, cysteine, or reduced glutathione, the reaction products of the two enzymes are identical and have been identified tentatively as thioether derivatives of DOPA. Theoretically, the oxidation of L-DOPA by TH may contribute to the formation of neuromelanin (pheomelanin) in catecholaminergic neurons and in the metabolism of DOPA to reactive intermediates that can react with free thiol groups in cellular proteins. The DOPA oxidase activity of TH can lead to errors in the estimation of in vivo or in vitro TH activity, and currently used assay protocols may have to be modified to avoid interference from this activity.

Juncos JL, Fabbrini G, Mouradian MM, Serrati C, Chase TN. Dietary influences on the antiparkinsonian response to levodopa. Arch Neurol. 1987 Oct;44(10):1003-1005.
Abstract: The ability of dietary factors to modify the response to levodopa was evaluated in six patients with idiopathic Parkinson's disease who manifested fluctuations in motor performance. The single oral administration of a high-protein formula substantially elevated plasma large neutral amino acid levels, and prematurely terminated the antiparkinsonian response to levodopa/carbidopa. In contrast, during oral or intravenous administration of levodopa, the ingestion of diets meeting the recommended daily allowance (RDA) for protein had no significant effect on plasma levodopa or large neutral amino acid levels or variance, nor on parkinsonian scores or variance. The results suggest that while protein intake in excess of the RDA can diminish the antiparkinsonian response to orally administered levodopa/carbidopa in patients with advanced disease, diets adhering to RDA protein guidelines have no clinically appreciable effect.

Kurlan R. Dietary therapy for motor fluctuations in Parkinson's disease . Arch Neurol. 1987;4:1119-1121. (Editorial)

Long, JW. The Essential Guide to Prescription Drugs 1992. New York: Harper Perennial, 1991.

Mena I and Cotzias GC. Protein intake and treatment of Parkinson's disease with levodopa. NEJM. 1975;292:181-184.

Molina JA, Jimenez-Jimenez FJ, Gomez P, Vargas C, Navarro JA, Orti-Pareja M, Gasalla T, Benito-Leon J, Bermejo F, Arenas J. Decreased cerebrospinal fluid levels of neutral and basic amino acids in patients with Parkinson's disease. J Neurol Sci 1997 Sep 10;150(2):123-127.
Abstract: We measured the CSF levels of 21, and the plasma levels of 26, amino acids in 31 patients with Parkinson's disease (PD) and in 45 matched controls. We used an ion-exchange chromatography method. When compared to controls, PD patients had lower CSF levels of taurine, alanine, valine, leucine, isoleucine, ethanolamine, citrulline, ornithine, lysine, histidine, arginine, and alpha-aminobutyric acid. PD patients not treated with levodopa or with dopamine agonists had higher CSF tyrosine and phenylalanine levels than those not treated with these drugs and also than controls. PD patients had higher plasma levels of phosphoserine, threonine, methionine, tyrosine, sarcosine and alpha-aminoadipic acid, and lower plasma levels of valine, leucine, and tryptophan, than controls. The CSF/plasma ratio of many of these amino acids was significantly lower in PD patients than those of controls, suggesting that PD patients might have a dysfunction in the transport of neutral and basic amino acids across the blood-brain barrier.

Nutt JG, Woodward WR, Hammerstad JP, Carter JH, Anderson JL. The "on-off" phenomenon in Parkinson's disease. N Engl J Med 1984 Feb 23;310(8):483-488.
Abstract: To determine whether the oscillating clinical response to levodopa in Parkinson's disease (the "on-off" phenomenon) reflects fluctuations in absorption and transport of the drug, we investigated this phenomenon in nine patients with an oscillating motor state. We studied the response to continuous infusion of levodopa and the effects of meals on the plasma levodopa concentrations and on the clinical response during oral and intravenous administration of the drug. Meals reduced peak plasma levodopa concentrations by 29 per cent and delayed absorption by 34 minutes. Bypassing absorption by constant infusion of the drug produced a stable clinical state lasting for 12 hours in all of six patients and for up to 36 hours in some. High-protein meals or oral phenylalanine, leucine, or isoleucine (100 mg per kilogram of body weight) reversed the therapeutic effect of infused levodopa without reducing plasma levodopa concentrations. Glycine and lysine at identical doses had no effect. We conclude that interference with absorption of levodopa by food and by competition between large neutral amino acids and levodopa for transport from plasma to the brain may be partly responsible for the fluctuating clinical response in patients with Parkinson's disease.

Pincus JH, Barry KM. Influence of dietary protein on motor fluctuations in Parkinson's disease. Arch Neurol. 1987;44:270-272.
Abstract: On a nearly zero protein diet, 11 patients with Parkinson's disease with the "on-off" effect demonstrated great sensitivity to levodopa (L-dopa)-carbidopa and reduced fluctuations. Eight patients required a 41% reduction in total L-dopa dosage and discontinuation of all adjuvant therapy to reduce the preponderance of chorea. On a high-protein diet, all patients were immobilized by bradykinesia for most of the day. A low-protein dietary regimen during the daytime offers an important technique for the control of fluctuations in patients with Parkinson's disease who are receiving L-dopa-carbidopa.

Pincus JH, Barry KM. Plasma levels of amino acids correlated with motor fluctuations in Parkinsonism. Arch Neurol. 1987;44:1006-1009.
Abstract: Seven patients with Parkinson's disease who experienced severe motor fluctuations in response to levodopa were studied in detail with relation to the effect of dietary protein on their motor function. The levodopa dose for each patient was not changed during the period of study, and no other antiparkinsonian drugs were used. Regular and high-protein diets resulted in a marked elevation in the plasma concentrations of large neutral amino acids (LNAAs) that are known to compete with levodopa for transport across the blood-brain barrier. Despite elevated plasma levodopa levels, all patients with elevated LNAA levels experienced parkinsonian symptoms. When the amino acid level dropped while plasma levodopa levels were elevated, patients experienced relief of these symptoms. On a low-protein diet, LNAA levels remained low and all patients were consistently dyskinetic throughout the day, even though the mean plasma levodopa levels were somewhat lower than when the patients consumed a high-protein diet. A redistribution diet that is virtually protein free until supper and then unrestricted until bedtime is tolerated by patients because this simple manipulation permits near-normal daytime motor function.

Pincus JH, Barry KM. Dietary method for reducing fluctuation in Parkinson's disease. Yale J Biol Med. 1987 Mar-Apr;60(2):133-137.
Abstract: Motor fluctuations and non-response to carbidopa-levodopa (Sinemet) therapy are major problems in the long-term management of Parkinson's disease. Levodopa manipulation, addition of adjuvants, and drug holidays are often unsuccessful. Others have shown that the clinical state of stabilized Parkinsonians can be reversed with intravenous administration of large neutral amino acids. Reasoning that dietary protein might precipitate motor oscillations and non-response, a low-protein daytime diet (7 g) was offered to fifteen patients. Eighty-six percent of this sample demonstrated immediate sensitivity to Sinemet. While on a low-protein diet, patients' clinical function was predominantly choreatic. Eight patients required a 10-60 percent reduction in their daily levodopa dose in order to minimize this choreatic tendency. Discontinuation of adjuvants did not compromise motor independence. Conversely, while on a high-protein diet (160 g), patients were predominantly immobile with markedly elevated plasma amino acid and levodopa levels. Consequently, elimination of dietary protein from breakfast and lunch can offer an effective and easily modified method for the amelioration of motor fluctuations and non-response to Sinemet in Parkinson's disease during working hours.

Pincus JH, Barry KM. Protein redistribution diet restores motor function in patients with dopa-resistant "off" periods. Neurology. 1988;38:481-483.
Abstract: Sixteen parkinsonians with acquired drug-resistant "off" periods without dyskinesia were placed on a diet in which virtually all protein was concentrated in the evening meal. Restoration of sensitivity to levodopa resulted in 88%. Ten patients (62%) have continued to comply with the diet for 7 months (mean). Two patients were studied in detail. Immobility correlated with elevated plasma levels of large neutral amino acids (LNAA), normality with low LNAA.

Riley D, Lang AE. Practical application of a low-protein diet for Parkinson's disease. Neurology. 1988;38:1026-1031.
Abstract: Thirty-eight patients with Parkinson's disease were treated with a protein-restricted diet in addition to their usual drug regime. Patients who had failed to obtain a significant response to levodopa previously did not benefit. Sixty percent of those with fluctuations in response to levodopa improved, primarily obtaining an increase in the ratio of "on" to "off" hours. Benefit was always noted within a week of diet initiation. The diet was well tolerated with a low incidence of side effects, which could usually be reversed by a reduction in levodopa dosage. A low-protein diet is a simple adjunct to levodopa therapy that can be readily instituted on an outpatient basis. It may improve even those patients with fluctuations who have failed to obtain optimal benefit from all forms of manipulation of the dosage schedule of levodopa or the addition of newer ancillary medications.

Sanchis G, Mena MA, Martin del Rio R, Morales B, Casarejo MJ, de Yebenes MJ, Tabernero C, Jimenez A, de Yebenes JG. [Effect of a controlled low-protein diet on the pharmacological response to levodopa and on the plasma levels of L-dopa and amino acids in patients with Parkinson's disease]. Arch Neurobiol (Madr). 1991 Nov-Dec;54(6):296-302. [Article in Spanish]
Abstract: Levodopa is the treatment of choice in Parkinson's disease, but a high percentage of patients develop complications in the response, including fluctuations, after some years of treatment. Although the origin of fluctuations is unknown, these could be, at least partly, attributed to pharmacokinetic factors. Aromatic aminoacids interfere in the absorption and brain penetration of levodopa, and lowering protein intake improves the quality of the response. The continuation of a low-protein diet is difficult for some patients. In this way, to know if these diet effects are noticeable in an acute period would be interesting, in order to select groups of patients who were susceptible to improve with this treatment. In this report we have studied the acute effect of a low protein diet on the pharmacological response to levodopa, and the plasmatic levels of L-Dopa, 3-OM-Dopa and large neutral aminoacids. Protein restriction improves clinical response to levodopa, although the mechanisms of this improvement remain unknown.

Trovato, A, et al. Drug-nutrient interactions. Am Family Phys 1991;44:1651-1658.

Wurtman R et al. Facilitation of levodopa-induced dyskinesias by dietary carbohydrates. NEJM. 1988;319:1288-1289. (Letter)