J Clin Pharmacol
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0091270009336735v1
49/7/856    most recent
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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.


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