Levodopa and the Progression of Parkinson's Disease
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《新英格兰医药杂志》
To the Editor: The measurements of motor responses after treatment with levodopa reported by the Parkinson Study Group (Dec. 9 issue)1 were taken too soon. The brief half-life of blood-borne levodopa is not related to the very slow rates of accumulation and depletion of dopamine retained in the limbic system. Ignoring paired facts that both the full effectiveness and the full limbic depletion of ingested levodopa require nearly 10 weeks, this study obtained skewed results by measuring movement only 2 weeks after the withdrawal of levodopa therapy. The full decline in motor function as the level of limbic dopamine drops below the threshold level begins to appear only after 2 to 3 weeks and is completely evident after 10 weeks. (The development of the on–off phenomenon has a different origin.)
Had this study measured motor function after 10 weeks instead of 2, I think it would have found motor results that corresponded to the findings of levodopa-inflicted cell loss that would have conformed to all previous studies: an accelerated decline in motor function as a result of levodopa therapy, as compared with placebo. This study, by measuring motor function too soon, dangerously encourages the use of larger starting doses of levodopa.2
Janice L. Walton-Hadlock, L.Ac.
Five Branches Institute
Santa Cruz, CA 95065
pdinfo@cruzio.com
References
The Parkinson Study Group. Levodopa and the progression of Parkinson's disease. N Engl J Med 2004;351:2498-2508.
Walton-Hadlock J. Medications of Parkinson's disease, or, once upon a pill: patient experiences with dopamine-enhancing drugs and supplements. Santa Cruz, Calif.: Parkinson's Recovery Project, 2003:43-4.
The authors reply: Ms. Walton-Hadlock emphasizes a caveat we mentioned in the Discussion section of our article1: a two-week period for washout from levodopa may have been insufficient for full elimination of its symptomatic benefit. A longer period without levodopa would probably result in dropouts, owing to prolonged parkinsonism. A two-week washout has been reported to achieve near-complete loss of benefit.2,3 We know of no controlled studies that support Walton-Hadlock's statement that 10 weeks is required for levodopa to lose its symptomatic benefit. Future investigators should consider a study design that does not depend on the return of symptoms, such as a delayed-start design. This design, also known as a randomized-start design, incorporates an early phase in which subjects are randomly assigned to either active medication or placebo and then a later phase in which both groups receive active medication, with blinding intact.
We disagree that the motor features of Parkinson's disease are related to limbic dopamine levels. Rather, all evidence indicates that striatal dopamine is critical.4 We know of no controlled studies that support the statement that levodopa therapy accelerates a decline in motor function. In fact, levodopa therapy improves motor function, which is why it is used.
We also wish to emphasize that although our imaging data showed greater decline among patients in the levodopa group, these data do not indicate a "levodopa-inflicted cell loss" but, as we said, may have several explanations.
Stanley Fahn, M.D.
Columbia University
New York, NY 10032
fahn@neuro.columbia.edu
Karl Keiburtz, M.D.
University of Rochester
Rochester, NY 14620
Caroline M. Tanner, M.D., Ph.D.
Parkinson's Institute
Sunnyvale, CA 94089
Had this study measured motor function after 10 weeks instead of 2, I think it would have found motor results that corresponded to the findings of levodopa-inflicted cell loss that would have conformed to all previous studies: an accelerated decline in motor function as a result of levodopa therapy, as compared with placebo. This study, by measuring motor function too soon, dangerously encourages the use of larger starting doses of levodopa.2
Janice L. Walton-Hadlock, L.Ac.
Five Branches Institute
Santa Cruz, CA 95065
pdinfo@cruzio.com
References
The Parkinson Study Group. Levodopa and the progression of Parkinson's disease. N Engl J Med 2004;351:2498-2508.
Walton-Hadlock J. Medications of Parkinson's disease, or, once upon a pill: patient experiences with dopamine-enhancing drugs and supplements. Santa Cruz, Calif.: Parkinson's Recovery Project, 2003:43-4.
The authors reply: Ms. Walton-Hadlock emphasizes a caveat we mentioned in the Discussion section of our article1: a two-week period for washout from levodopa may have been insufficient for full elimination of its symptomatic benefit. A longer period without levodopa would probably result in dropouts, owing to prolonged parkinsonism. A two-week washout has been reported to achieve near-complete loss of benefit.2,3 We know of no controlled studies that support Walton-Hadlock's statement that 10 weeks is required for levodopa to lose its symptomatic benefit. Future investigators should consider a study design that does not depend on the return of symptoms, such as a delayed-start design. This design, also known as a randomized-start design, incorporates an early phase in which subjects are randomly assigned to either active medication or placebo and then a later phase in which both groups receive active medication, with blinding intact.
We disagree that the motor features of Parkinson's disease are related to limbic dopamine levels. Rather, all evidence indicates that striatal dopamine is critical.4 We know of no controlled studies that support the statement that levodopa therapy accelerates a decline in motor function. In fact, levodopa therapy improves motor function, which is why it is used.
We also wish to emphasize that although our imaging data showed greater decline among patients in the levodopa group, these data do not indicate a "levodopa-inflicted cell loss" but, as we said, may have several explanations.
Stanley Fahn, M.D.
Columbia University
New York, NY 10032
fahn@neuro.columbia.edu
Karl Keiburtz, M.D.
University of Rochester
Rochester, NY 14620
Caroline M. Tanner, M.D., Ph.D.
Parkinson's Institute
Sunnyvale, CA 94089