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Levodopa therapy, as originally established by George Cotzias [2, 3], is the m ost powerful treatment for Parkinson’s disease (PD). Levodopa’s toxicity to ne urons in vitro has raised concerns if it might hasten the progression of PD, alt hough in vivo animal studies suggest it may be neuroprotective. To discuss the r esults of the ELLDOPA trial that was carried out to determine if levodopa therap y influences the rate of progression of Parkinson’s disease (PD). ELLDOPA was a multicenter, parallel-group, double-blind, dosage-ranging, randomized, contr olled clinical trial. Academic movement disorders clinics at 38 sites in the Uni ted States and Canada. Three hundred and sixty-one patients with early PD of le ss than 2 years’duration who did not require symptomatic therapy. Subjects were randomly assigned to one of four treatment groups: carbidopa/levodopa 12.5/50 m g t. i. d. (N=92), 25/100 mg t. i. d. (N=88), 50/200 mg t. i. d. (N=91), or matc hing placebo (N=90). The dosage was gradually escalated over 9 weeks and then ma intained until Week 40, at which time active treatment was withdrawn over 3 days . After 2 weeks without active treatment (Week 42), a final assessment of PD sev erity was obtained. The prespecified primary clinical outcome was the change in the total Unified Parkinson’s Disease Rating Scale (UPDRS) between baseline and Week 42, comparing the four treatment groups. The primary neuroimaging componen t of the study in a subgroup of 142 subjects was the percent change in striatal( 123)iodine 2-β-carboxymethoxy-3-β-(4-iodophe nyl)tropane (β-CIT) uptak e between baseline and Week 40 visits. The neuroimaging substudy utilized single photon emission computed tomography (SPECT) of the dopamine transporter. All do sages of levodopa exerted clinical benefit compared to placebo on the UPDRS scor es throughout the study, including 2 weeks after discontinuing levodopa. The UPD RS scores at Week 42 failed to reach the level encountered in the placebo group (change of 7.8±9.0, 1.9±6.0, 1.9±6.9, and - 1.4±7.8, for placebo, 150 mg/day, 300 mg/ day, and 600 mg/day, respectively, p < 0.0001). Nausea (p=0.001) and dyskinesias (p=0.0001) were more common in the l evodopa groups, especially with the higher dosages. Freezing appeared around the same time, but was more common in the placebo (14 %)and 150 mg/day group (10 %). The percent decline of β-CIT uptake in the striatum was significantly mor e pronounced in the levodopa groups than the placebo group (-7.2%, -4%, -6 %, and -1.4%in 600 mg/day, 300 mg/day, 150 mg/day, and placebo, respectively; p=0.035). The clinical outcomes not only indicate that levodopa is effective in a dose-dependent manner in overcoming the signs and symptoms of PD, they also support the concept that the drug does not hasten the disease progression, but r ather may slow down the rate of the disease. The clinical study failed to demons trate any evidence of levodopa worsening early PD. However, the β-CIT SPECT su bstudy indicates the opposite effect, namely that levodopa causes a more rapid d ecline in the integrity of the dopamine transporter located in the nigrostriatal nerve terminals in the striatum. These contradictory findings warrant further i nvestigation into the effect of levodopa on PD. The ELLDOPA study was the first levodopa dose-response study ever conducted. It showed that dose is a factor in the cause of producing motor complications of dyskinesias and wearing-off, and that these can develop as early as 5 to 6 months. On the other hand, freezing o f gait could be delayed or its occurrence reduced by high dosage levodopa, compa red to placebo or low-dose levodopa. Withdrawal of levodopa over a 3-day step -down can be safely carried out without inducing the neuroleptic-like syndrome . The UPDRS was shown to be a reliable linear marker for disease progression. Th e ELLDOPA study also called into question the interpretation of β-CIT SPECT in the presence of dopaminergic agents. Neuroimaging in ELLDOPA also showed that s ome people diagnosed with early PD do not have a dopaminergic deficit, calling i nto question how difficult the correct diagnosis may be in people with early sym ptoms of PD.
Levodopa’s therapy, as originally established by George Cotzias [2, 3], is the most powerful treatment for Parkinson’s disease (PD). Levodopa’s toxicity to ne urons in vitro has raised concerns if it might have the the progression of PD, alt hough in To discuss the résults of the ELLDOPA trial that was carried out to determine if levodopa therap y influences the rate of progression of Parkinson’s disease (PD). ELLDOPA was a multicenter, parallel-group, double -blind, dosage-ranging, randomized, contr olled clinical trial. Academic movement disorders clinics at 38 sites in the Uni ted States and Canada. Three hundred and sixty-one patients with early PD of le ss than 2 years’duration who did not Subjects were randomly assigned to one of four treatment groups: carbidopa / levodopa 12.5 / 50 mg tid (N = 92), 25/100 mg tid (N = 88), 50/200 mg tid , or matc hing placebo (N = 90). The dosage was grad The prespecified primary clinical outcome was Week 9, and the final assessment of PD sevity was obtained. The prespecified primary clinical outcome was the change in the total Unified Parkinson’s Disease Rating Scale (UPDRS) between baseline and Week 42, comparing the four treatment groups. The primary neuroimaging componen t of the study in a subgroup of 142 subjects was the percent change in striatal (123) iodine 2-β-carboxymethoxy-3-β- (4-iodophe nyl) tropane (β-CIT) uptak e between baseline and Week 40 visits. The neuroimaging substudypsed single photon emission computed tomography (SPECT) of the dopamine transporter. All do sages of levodopa exerted clinical benefit compared to placebo on the UPDRS scor es throughout the study, including 2 weeks after discontinuing levodopa. The UPD RS scores at Week 42 failed to reach the level encountered in the placebo group (cfor each of placebo, 150 mg / day, 300 mg / day, and 600 mg / day, respectively, p <0.0001). Nausea (p = 0.001) and dyskinesias (p = 0.0001) were more common in the l evodopa groups, especially with the higher dosages. Freezing had the same time, but was more common in the placebo (14%) and 150 mg / day group %). The percent decline of β-CIT uptake in the striatum was significantly mor e pronounced in the levodopa groups than the placebo group (-7.2%, -4%, -6%, and -1.4% in 600 mg / day, 300 mg / day, 150 mg / day, and placebo, respectively; p = 0.035). The clinical outcomes not only in levodopa is effective in a dose-dependent manner in over the signs and symptoms of PD, they also support the concept that the drug does not have the disease progression, but r ather may slow down the rate of the disease. The clinical study failed to demons trate any evidence of levodopa worsening early PD. However, the β-CIT SPECT su bstu dy indicates the opposite effect, which that levodopa causes a more rapid d ecline in the integrity of the dopamine transporter located in the nigrostriatal nerve terminals in the striatum. was the first levodopa dose-response study ever conducted. It showed that dose is a factor in the cause of of motoromots of dyskinesias and wearing-off, and that these can develop as early as 5 to 6 months. On the other hand, freezing of gait could be delayed or its occurrence reduced by high dosage levodopa, compa red to placebo or low-dose levodopa. Withdrawal of levodopa over a 3-day step-down can be safely carried out without inducing the neuroleptic-like syndrome. The UPDRS was shown to be reliable marker for disease progression. Th e ELLDOPA study also called into the interpretation of β-CIT SPECT in the presence of dopaminergic agents. Neuroim aging in ELLDOPA also showed that s ome people diagnosed with early PD do not have a dopaminergic deficit, calling i nto question how difficult the correct diagnosis may be in people with early sym ptoms of PD.