title: Levodopa and the progression of Parkinson's disease.
abstract: BACKGROUND
  Despite the known benefit of levodopa in reducing the symptoms of Parkinson's disease, concern has been expressed that its use might hasten neurodegeneration. This study assessed the effect of levodopa on the rate of progression of Parkinson's disease.
  
  
  METHODS
  In this randomized, double-blind, placebo-controlled trial, we evaluated 361 patients with early Parkinson's disease who were assigned to receive carbidopa-levodopa at a daily dose of 37.5 and 150 mg, 75 and 300 mg, or 150 and 600 mg, respectively, or a matching placebo for a period of 40 weeks, and then to undergo withdrawal of treatment for 2 weeks. The primary outcome was a change in scores on the Unified Parkinson's Disease Rating Scale (UPDRS) between baseline and 42 weeks. Neuroimaging studies of 142 subjects were performed at baseline and at week 40 to assess striatal dopamine-transporter density with the use of iodine-123-labeled 2-beta-carboxymethoxy-3-beta-(4-iodophenyl)tropane ([123I]beta-CIT) uptake.
  
  
  RESULTS
  The severity of parkinsonism increased more in the placebo group than in all the groups receiving levodopa: the mean difference between the total score on the UPDRS at baseline and at 42 weeks was 7.8 units in the placebo group, 1.9 units in the group receiving levodopa at a dose of 150 mg daily, 1.9 in those receiving 300 mg daily, and -1.4 in those receiving 600 mg daily (P<0.001). In contrast, in a substudy of 116 patients the mean percent decline in the [123I]beta-CIT uptake was significantly greater with levodopa than placebo (-6 percent among those receiving levodopa at 150 mg daily, -4 percent in those receiving it at 300 mg daily, and -7.2 percent among those receiving it at 600 mg daily, as compared with -1.4 percent among those receiving placebo; 19 patients with no dopaminergic deficits on the baseline scans were excluded from the analysis) (P=0.036). The subjects receiving the highest dose of levodopa had significantly more dyskinesia, hypertonia, infection, headache, and nausea than those receiving placebo.
  
  
  CONCLUSIONS
  The clinical data suggest that levodopa either slows the progression of Parkinson's disease or has a prolonged effect on the symptoms of the disease. In contrast, the neuroimaging data suggest either that levodopa accelerates the loss of nigrostriatal dopamine nerve terminals or that its pharmacologic effects modify the dopamine transporter. The potential long-term effects of levodopa on Parkinson's disease remain uncertain.
authors.affiliation: Columbia University, New York, USA. fahn@neuro.columbia.edu
authors.forename: Stanley
authors.initials: S
authors.lastname: Fahn
authors.forename: David
authors.initials: D
authors.lastname: Oakes
authors.forename: Ira
authors.initials: I
authors.lastname: Shoulson
authors.forename: Karl
authors.initials: K
authors.lastname: Kieburtz
authors.forename: Alice
authors.initials: A
authors.lastname: Rudolph
authors.forename: Anthony
authors.initials: A
authors.lastname: Lang
authors.forename: C Warren
authors.initials: CW
authors.lastname: Olanow
authors.forename: Caroline
authors.initials: C
authors.lastname: Tanner
authors.forename: Kenneth
authors.initials: K
authors.lastname: Marek
mesh_terms: D000368:Aged; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002230:Carbidopa / Q000008:administration & dosage / Q000627:therapeutic use*; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000378:metabolism; D018450:Disease Progression; D050483:Dopamine Plasma Membrane Transport Proteins; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007980:Levodopa / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010300:Parkinson Disease / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D000978:Antiparkinson Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D004338:Drug Combinations; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D007980:Levodopa; D002230:Carbidopa