BACKGROUND: Ever since the pioneering reports in the 60s, 
L-3,4-Dioxyphenylalanine (levodopa) has represented the gold standard for the 
treatment of Parkinson's Disease (PD). However, long-term levodopa (LD) 
treatment is frequently associated with fluctuations in motor response with 
serious impact on patient quality of life. The pharmacokinetic and 
pharmacodynamic properties of LD are pivotal to such motor fluctuations: 
discontinuous drug delivery, short half-life, poor bioavailability, and narrow 
therapeutic window are all crucial for such fluctuations. During the last 60 
years, several attempts have been made to improve LD treatment and avoid 
long-term complications.
METHODS: Research and trials to improve the LD pharmacokinetic since 1960s are 
reviewed, summarizing the progressive improvements of LD treatment.
RESULTS: Inhibitors of peripheral amino acid decarboxylase (AADC) have been 
introduced to achieve proper LD concentration in the central nervous system 
reducing systemic adverse events. Inhibitors of catechol-O-methyltransferase 
(COMT) increased LD half-life and bioavailability. Efforts are still being made 
to achieve a continuous dopaminergic stimulation, with the combination of oral 
LD with an AADC inhibitor and a COMT inhibitor, or the intra-duodenal 
water-based LD/ carbidopa gel. Further approaches to enhance LD efficacy are 
focused on new non-oral administration routes, including nasal, intra-duodenal, 
intrapulmonary (CVT-301) and subcutaneous (ND0612), as well as on novel ER 
formulations, including IPX066, which recently concluded phase III trial.
CONCLUSION: New LD formulations, oral compounds as well as routes have been 
tested in the last years, with two main targets: achieve continuous dopaminergic 
stimulation and find an instant deliver route for LD.