J Clin Pharmacol
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Sign In to gain access to subscriptions and/or personal tools.
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
0091270009336735v1
49/7/856    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Google Scholar
Right arrow Articles by Addy, C.
Right arrow Articles by Wagner, J.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Addy, C.
Right arrow Articles by Wagner, J.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

PHARMACODYNAMICS

Single-Dose Administration of MK-0657, an NR2B-Selective NMDA Antagonist, Does Not Result in Clinically Meaningful Improvement in Motor Function in Patients With Moderate Parkinson's Disease

Carol Addy, MD, MMSc, Chris Assaid, PhD, David Hreniuk, BS, Mark Stroh, PhD, Yang Xu, PhD, W. Joseph Herring, MD, PhD, Aaron Ellenbogen, DO, H. A. Jinnah, MD, PhD, Louis Kirby, MD, Mark T. Leibowitz, MD, R. Malcolm Stewart, MD, Daniel Tarsy, MD, James Tetrud, MD, S. Aubrey Stoch, MD, Keith Gottesdiener, MD and John Wagner, MD, PhD

From Merck & Co, Inc, Whitehouse Station, New Jersey (Dr Addy, Dr Assaid, Mr Hreniuk, Dr Stroh, Dr Xu, Dr Herring, Dr Stoch, Dr Gottesdiener, Dr Wagner); Quest Research Institute, Bingham Farms, Michigan (Dr Ellenbogen); Department of Neurology, Johns Hopkins Hospital, Baltimore, Maryland, present address Department of Neurology, Emory University, Atlanta, Georgia (Dr Jinnah); Pivotal Research Center, Peoria, Arizona, present address Provista Life Sciences, Phoenix, Arizona (Dr Kirby); California Clinical Trials, Glendale, California, present address CEDRA Clinical Research, Austin, Texas (Dr Leibowitz); Radiant Research, Dallas, Texas, present address Texas Health Presbyterian, Dallas, Texas (Dr Stewart); Beth Israel Deaconess Medical Center, Boston, Massachusetts (Dr Tarsy); and The Parkinson's Institute, Sunnyvale, California (Dr Tetrud).

The glutamatergic system is thought to contribute to the motor disturbances observed in Parkinson's disease. Blockade of glutamatergic activity by a selective antagonist of the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor is associated with improvement in motor symptoms in a preclinical model of Parkinson's disease. A randomized, double-blind, double-dummy, placebo-controlled, 3-period crossover study was conducted in patients with moderate Parkinson's disease to evaluate the pharmacologic activity of MK-0657, an NR2B-selctive NMDA receptor antagonist. Patients (n = 16) received single oral doses of MK-0657 7 mg, carbidopa/levodopa 25/250 mg (LD) as a positive control, and placebo, after which motor function was serially evaluated by means of the Unified Parkinson's Disease Rating Scale–Motor Examination (UPDRS-ME). LD administration resulted in significant improvement in the UPDRS-ME relative to placebo (P = .025), confirming the sensitivity of the test paradigm; however, the UPDRS-ME change following MK-0657 administration showed no improvement compared with placebo (P = .110) despite exceeding the target MK-0657 plasma concentration of 400 nM. Although the administration of MK-0657 was generally well tolerated, it was associated with increases in systolic and diastolic blood pressure relative to placebo. The results of this study do not support ongoing clinical development of MK-0657 as a novel monotherapy for Parkinson's disease.

Key Words: Parkinson's disease • glutamate receptor • NMDA • NR2B

Address for reprints: Carol Addy, MD, MMSc, Merck Research Laboratories, Department of Clinical Pharmacology, 33 Avenue Louis Pasteur, Boston, MA 02115; e-mail: carol_addy{at}merck.com.


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?




HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Copyright © 2009 by the American College of Clinical Pharmacology