A double-blind, placebo-controlled study of the safety, tolerability and pharmacokinetics of CP-101,606 in patients with a mild or moderate traumatic brain injury

Randall E. Merchant, Ross Bullock, Cynthia A. Carmack, Ajit K. Shah, Keith D. Wilner, Grant Ko, Stephen A. Williams

Research output: Contribution to journalArticle

84 Citations (Scopus)

Abstract

CP-101,606 is a postsynaptic antagonist of the glutamate-mediated NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor. When administered intravenously (i.v.) at the time of injury, CP-101,606 is neuroprotecttve in animal models of traumatic brain injury (TBI) and ischemia. Minimal adverse effects have been observed in normal human volunteers given i.v. doses of up to 3 mg/kg/hr for 72 hours. The objective of the present clinical trial was to assess the safety, pharmacokinetics, and tolerability of CP-101,606 infused for various times in patients who had suffered either an acute moderate or mild TBI (Glasgow Coma Score 9-14) or hemorrhagic stroke. Patients began receiving treatment within 12 hours of brain injury. A total of 53 subjects (45 with TBI and 8 with stroke) were randomized in a double-blind fashion to receive CP-101,606 or placebo (4 drug:1 placebo). Drug/placebo was administered by i.v. infusion (0.75 mg/kg/hr) for 2 hours and then stopped (n = 25) or continued for 22 hours (n = 4) or 70 hours (n = 24) at a rate of 0.37 mg/kg/hr. Mean plasma drug concentrations were well above the predicted therapeutic concentration of 200 ng/ml within two hours of initiating treatment and were sustained as long as drug was infused. All the patients tolerated their drug/placebo treatment, and there were no clinically significant cardiovascular or hematological abnormalities in either group. A Neurobehavioral Rating Scale, used to detect personality changes and behavioral disturbances, indicated that all subjects showed an improvement from their postinjury, predosing baseline but did not significantly differ from each other with respect to type of head injury and/or treatment with drug or placebo. Modified Kurtzke Scoring also showed a similar pattern of improvement irrespective of type of head injury or drug/placebo treatment. This study suggests that CP-101,606, infused for up to 72 hours has no psychotropic effects and is well-tolerated in patients who have sustained a mild or moderate TBI or hemorrhagic stroke.

Original languageEnglish
Pages (from-to)42-50
Number of pages9
JournalAnnals of the New York Academy of Sciences
Volume890
StatePublished - Dec 1 1999
Externally publishedYes

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Pharmacokinetics
Brain
Placebos
Safety
Drug therapy
Pharmaceutical Preparations
Stroke
Craniocerebral Trauma
Excitatory Amino Acid Antagonists
Therapeutics
Brain Concussion
N-Methyl-D-Aspartate Receptors
Animals
Coma
Traumatic Brain Injury
traxoprodil mesylate
Drugs
Controlled
Placebo
Brain Ischemia

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

A double-blind, placebo-controlled study of the safety, tolerability and pharmacokinetics of CP-101,606 in patients with a mild or moderate traumatic brain injury. / Merchant, Randall E.; Bullock, Ross; Carmack, Cynthia A.; Shah, Ajit K.; Wilner, Keith D.; Ko, Grant; Williams, Stephen A.

In: Annals of the New York Academy of Sciences, Vol. 890, 01.12.1999, p. 42-50.

Research output: Contribution to journalArticle

Merchant, Randall E. ; Bullock, Ross ; Carmack, Cynthia A. ; Shah, Ajit K. ; Wilner, Keith D. ; Ko, Grant ; Williams, Stephen A. / A double-blind, placebo-controlled study of the safety, tolerability and pharmacokinetics of CP-101,606 in patients with a mild or moderate traumatic brain injury. In: Annals of the New York Academy of Sciences. 1999 ; Vol. 890. pp. 42-50.
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