title: A pulmonary formulation of L-dopa enhances its effectiveness in a rat model of Parkinson's disease.
abstract: The efficacy of oral L-dopa becomes problematic with the progression of Parkinson's disease, due in large part to a lost ability to accommodate L-dopa's inherently poor pharmacokinetics. Pulmonary delivery represents a novel approach to reducing this problem. L-dopa was formulated into inhalable (Alkermes AIR) particles, and its pharmacokinetics and pharmacodynamics compared with those of an oral formulation. Pulmonary administration of L-dopa (2 mg) to rats resulted in a rapid elevation of plasma levels (C(max) = 4.8 +/- 1.10 microg/ml at 2 min), whereas oral administration of L-dopa produced a much delayed and lower C(max) (1.8 +/- 0.40 microg/ml at 30 min). In a rat model of Parkinson's disease (unilateral 6-hydroxydopamine lesion), the pulmonary formulation of L-dopa (0.5-2.0 mg) yielded more rapid and robust elevations in striatal L-dopa, dopamine, and dihydroxyphenylacetic acid levels, as well as 2.5 to 3.7 times as many c-fos-expressing striatal neurons. Moreover, motor function was significantly improved by 10 min after administration, with peak improvements occurring within 15 to 30 min. In contrast, considerably higher doses (6.8-10 mg) of orally administered L-dopa took over three times longer to produce similar effects. These results suggest that an inhalable formulation of l-dopa has superior pharmacokinetic properties and may provide patients with a more effective form of rescue therapy as well as being a reliable adjuvant or replacement for first-line oral therapy.
authors.affiliation: Alkermes Inc., Cambridge, MA, USA. rtbartus@ceregene.com
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Bartus
authors.forename: Dwaine
authors.initials: D
authors.lastname: Emerich
authors.forename: Pam
authors.initials: P
authors.lastname: Snodgrass-Belt
authors.forename: Karen
authors.initials: K
authors.lastname: Fu
authors.forename: Heather
authors.initials: H
authors.lastname: Salzberg-Brenhouse
authors.forename: Denise
authors.initials: D
authors.lastname: Lafreniere
authors.forename: Leah
authors.initials: L
authors.lastname: Novak
authors.forename: Ee-Sing
authors.initials: ES
authors.lastname: Lo
authors.forename: Thomas
authors.initials: T
authors.lastname: Cooper
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Basile
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D002626:Chemistry, Pharmaceutical; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D007980:Levodopa / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D007980:Levodopa