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Preclinical and clinical assessment of inhaled levodopa for OFF episodes in Parkinson's disease.

Abstract：

:Inhaled drugs offer advantages, such as rapid onset of action, but require formulations and delivery systems that reproducibly and conveniently administer the drug. CVT-301 is a powder formulation of levodopa delivered by a breath-actuated inhaler that has been developed for treating OFF episodes (motor fluctuations between doses of standard oral levodopa) in patients with Parkinson's disease (PD). We present preclinical, phase 1, and phase 2 results for CVT-301. In dogs insufflated with a levodopa powder, plasma levodopa peaked in all animals 2.5 min after administration; in contrast, in dogs dosed orally with levodopa plus carbidopa, plasma levodopa was not detected until 30 min after administration. In 18 healthy persons, comparisons between inhaled CVT-301 and oral carbidopa/levodopa showed analogous differences in pharmacokinetics. Among 24 PD patients inhaling CVT-301 as a single 50-mg dose during an OFF episode, 77% showed an increase in plasma levodopa (>400 ng/ml) within 10 min versus 27% for oral dosing with carbidopa/levodopa at a 25-mg/100-mg dose. Improvements in timed finger tapping and overall motor function (Part III of the Unified Parkinson's Disease Rating Scale) were seen 5 and 15 min after administration, the earliest assessment time points. For average and best change, the improvements were statistically significant compared to placebo. The most common adverse event was cough; all cough events were mild to moderate, occurred at the time of inhalation, resolved rapidly, and became less frequent after initial dosing. These results support further development of CVT-301 for better management of PD.

journal_name

Sci Transl Med

journal_title

Science translational medicine

authors

Lipp MM,Batycky R,Moore J,Leinonen M,Freed MI

doi

10.1126/scitranslmed.aad8858

subject

Has Abstract

pub_date

2016-10-12 00:00:00

pages

360ra136

issue

360

eissn

1946-6234

issn

1946-6242

pii

8/360/360ra136

journal_volume

8

pub_type

杂志文章,多中心研究,随机对照试验

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