Improvement in mitochondrial dysfunction as a new surrogate efficiency measure for preclinical trials: Dose-response and time-window profiles for administration of the calcium channel blocker Ziconotide in experimental brain injury

B. H. Verweij, Jan Paul Muizelaar, F. C. Vinas, P. L. Peterson, Y. Xiong, C. P. Lee

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Object. Determining the efficacy of a drug used in experimental traumatic brain injury (TBI) requires the use of one or more outcome measures such as decreased mortality or fewer neurological and neuropsychological deficits. Unfortunately, outcomes in these test batteries have a fairly large variability, requiring relatively large sample sizes, and administration of the tests themselves is also very time consuming. The authors previously demonstrated that experimental TBI and human TBI induce mitochondrial dysfunction. Because mitochondrial dysfunction is easy to assess compared with neurobehavioral endpoints, it might prove useful as an outcome measure to establish therapeutic time windows and dose-response curves in preclinical drug testing. This idea was tested in a model of TBI in rats. Methods. Animals treated with the selective N-type voltage-sensitive calcium channel blocker Ziconotide (also known as SNX-111 and CI-1009) after cortical impact displayed significant improvement in brain mitochondrial function. When a single intravenous bolus injection of 4 mg/kg Ziconotide was given at different time intervals, ranging from 15 minutes before injury to 10 hours after injury, mitochondrial function was improved at all time points, but more so between 2 and 6 hours postinjury. The authors evaluated the effects on mitochondrial function of Ziconotide at different doses by administering 0.5 to 6 mg/kg as a single bolus injection 4 hours after injury, and found 4 mg/kg to be the optimum dose. Conclusions. The authors established these time-window profiles and dose-response curves on the basis of mitochondrial outcome measures in a total of 42 rats because there were such low standard deviations in these tests. Establishing similar time-window profiles and dose-response curves by using neurobehavioral endpoints would have required using 114 rats in much more elaborate experiments.

Original languageEnglish (US)
Pages (from-to)829-834
Number of pages6
JournalJournal of Neurosurgery
Volume93
Issue number5
StatePublished - 2000

Fingerprint

Calcium Channel Blockers
Brain Injuries
Reaction Time
Outcome Assessment (Health Care)
Wounds and Injuries
Intravenous Injections
Pharmaceutical Preparations
Sample Size
ziconotide
Injections
Mortality
Traumatic Brain Injury
Brain

Keywords

  • Cerebral mitochondria
  • Cerebral oxygen metabolism
  • Dose-response curve
  • Preclinical trial
  • Time-window profile
  • Traumatic brain injury

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)

Cite this

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title = "Improvement in mitochondrial dysfunction as a new surrogate efficiency measure for preclinical trials: Dose-response and time-window profiles for administration of the calcium channel blocker Ziconotide in experimental brain injury",
abstract = "Object. Determining the efficacy of a drug used in experimental traumatic brain injury (TBI) requires the use of one or more outcome measures such as decreased mortality or fewer neurological and neuropsychological deficits. Unfortunately, outcomes in these test batteries have a fairly large variability, requiring relatively large sample sizes, and administration of the tests themselves is also very time consuming. The authors previously demonstrated that experimental TBI and human TBI induce mitochondrial dysfunction. Because mitochondrial dysfunction is easy to assess compared with neurobehavioral endpoints, it might prove useful as an outcome measure to establish therapeutic time windows and dose-response curves in preclinical drug testing. This idea was tested in a model of TBI in rats. Methods. Animals treated with the selective N-type voltage-sensitive calcium channel blocker Ziconotide (also known as SNX-111 and CI-1009) after cortical impact displayed significant improvement in brain mitochondrial function. When a single intravenous bolus injection of 4 mg/kg Ziconotide was given at different time intervals, ranging from 15 minutes before injury to 10 hours after injury, mitochondrial function was improved at all time points, but more so between 2 and 6 hours postinjury. The authors evaluated the effects on mitochondrial function of Ziconotide at different doses by administering 0.5 to 6 mg/kg as a single bolus injection 4 hours after injury, and found 4 mg/kg to be the optimum dose. Conclusions. The authors established these time-window profiles and dose-response curves on the basis of mitochondrial outcome measures in a total of 42 rats because there were such low standard deviations in these tests. Establishing similar time-window profiles and dose-response curves by using neurobehavioral endpoints would have required using 114 rats in much more elaborate experiments.",
keywords = "Cerebral mitochondria, Cerebral oxygen metabolism, Dose-response curve, Preclinical trial, Time-window profile, Traumatic brain injury",
author = "Verweij, {B. H.} and Muizelaar, {Jan Paul} and Vinas, {F. C.} and Peterson, {P. L.} and Y. Xiong and Lee, {C. P.}",
year = "2000",
language = "English (US)",
volume = "93",
pages = "829--834",
journal = "Journal of Neurosurgery",
issn = "0022-3085",
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T1 - Improvement in mitochondrial dysfunction as a new surrogate efficiency measure for preclinical trials

T2 - Dose-response and time-window profiles for administration of the calcium channel blocker Ziconotide in experimental brain injury

AU - Verweij, B. H.

AU - Muizelaar, Jan Paul

AU - Vinas, F. C.

AU - Peterson, P. L.

AU - Xiong, Y.

AU - Lee, C. P.

PY - 2000

Y1 - 2000

N2 - Object. Determining the efficacy of a drug used in experimental traumatic brain injury (TBI) requires the use of one or more outcome measures such as decreased mortality or fewer neurological and neuropsychological deficits. Unfortunately, outcomes in these test batteries have a fairly large variability, requiring relatively large sample sizes, and administration of the tests themselves is also very time consuming. The authors previously demonstrated that experimental TBI and human TBI induce mitochondrial dysfunction. Because mitochondrial dysfunction is easy to assess compared with neurobehavioral endpoints, it might prove useful as an outcome measure to establish therapeutic time windows and dose-response curves in preclinical drug testing. This idea was tested in a model of TBI in rats. Methods. Animals treated with the selective N-type voltage-sensitive calcium channel blocker Ziconotide (also known as SNX-111 and CI-1009) after cortical impact displayed significant improvement in brain mitochondrial function. When a single intravenous bolus injection of 4 mg/kg Ziconotide was given at different time intervals, ranging from 15 minutes before injury to 10 hours after injury, mitochondrial function was improved at all time points, but more so between 2 and 6 hours postinjury. The authors evaluated the effects on mitochondrial function of Ziconotide at different doses by administering 0.5 to 6 mg/kg as a single bolus injection 4 hours after injury, and found 4 mg/kg to be the optimum dose. Conclusions. The authors established these time-window profiles and dose-response curves on the basis of mitochondrial outcome measures in a total of 42 rats because there were such low standard deviations in these tests. Establishing similar time-window profiles and dose-response curves by using neurobehavioral endpoints would have required using 114 rats in much more elaborate experiments.

AB - Object. Determining the efficacy of a drug used in experimental traumatic brain injury (TBI) requires the use of one or more outcome measures such as decreased mortality or fewer neurological and neuropsychological deficits. Unfortunately, outcomes in these test batteries have a fairly large variability, requiring relatively large sample sizes, and administration of the tests themselves is also very time consuming. The authors previously demonstrated that experimental TBI and human TBI induce mitochondrial dysfunction. Because mitochondrial dysfunction is easy to assess compared with neurobehavioral endpoints, it might prove useful as an outcome measure to establish therapeutic time windows and dose-response curves in preclinical drug testing. This idea was tested in a model of TBI in rats. Methods. Animals treated with the selective N-type voltage-sensitive calcium channel blocker Ziconotide (also known as SNX-111 and CI-1009) after cortical impact displayed significant improvement in brain mitochondrial function. When a single intravenous bolus injection of 4 mg/kg Ziconotide was given at different time intervals, ranging from 15 minutes before injury to 10 hours after injury, mitochondrial function was improved at all time points, but more so between 2 and 6 hours postinjury. The authors evaluated the effects on mitochondrial function of Ziconotide at different doses by administering 0.5 to 6 mg/kg as a single bolus injection 4 hours after injury, and found 4 mg/kg to be the optimum dose. Conclusions. The authors established these time-window profiles and dose-response curves on the basis of mitochondrial outcome measures in a total of 42 rats because there were such low standard deviations in these tests. Establishing similar time-window profiles and dose-response curves by using neurobehavioral endpoints would have required using 114 rats in much more elaborate experiments.

KW - Cerebral mitochondria

KW - Cerebral oxygen metabolism

KW - Dose-response curve

KW - Preclinical trial

KW - Time-window profile

KW - Traumatic brain injury

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