Clinical Trial: Acetylcholinesterase Inhibition and Orthostatic Hypotension in SC I

Study Status: Completed
Recruit Status: Unknown status
Study Type: Interventional

Official Title: Acetylcholinesterase Inhibition: A Novel Approach in the Treatment of Orthostatic Hypotension in SCI

Brief Summary: Due to de-centralized cardiovascular control, persons with spinal cord injury (SCI) experience blood pressure (BP) dysregulation which manifests in chronic hypotension with exacerbation during orthostatic positioning. Although many individuals with SCI remain asymptomatic to hypotension and orthostatic hypotension (OH), we recently reported reduced memory and marginally reduced attention and processing speed in hypotensive individuals with SCI compared to a normotensive cohort. Thus, we believe that treatment of overtly asymptomatic hypotension and OH in the SCI population is clinically warranted. Currently the FDA has approved only midodrine hydrochloride for the treatment of dizziness associated with OH and proof of efficacy is limited. Acetylcholinesterase inhibition for treatment of OH is a novel concept and has gained recent recognition in models of neurogenic OH (multiple system atrophy; pure autonomic failure, diabetic neuropathy). The physiological rationale of this concept is unique: acetylcholine (AcH) is the pre-ganglionic neurotransmitter of the sympathetic nervous system. Inhibition of acetylcholinesterase will limit the breakdown of AcH thereby facilitating vascular adrenergic tone and peripheral vasoconstriction. Acetylcholinesterase inhibition has been reported to be efficacious in models of both pre-ganglionic (multiple system atrophy) and post-ganglionic (pure autonomic failure, diabetic neuropathy) origin and persons with SCI reflect a model of a preganglionic disorder. In theory, if an individual has a complete autonomic lesion, acetylcholinesterase inhibition would not be expected to improve orthostatic BP because little/no neural traffic would be transmitted to the pre-synapse. However, individuals with an incomplete autonomic lesion may benefit from this class of agent. Researchers are currently investigating the orthostatic BP effects of acetylcholinesterase inhibition with pyridostigmine bromide (60 mg) in 10 individuals with complete (AIS A

Detailed Summary:

Due to de-centralized cardiovascular control, persons with spinal cord injury (SCI) experience blood pressure (BP) dysregulation which manifests in chronic hypotension with exacerbation during orthostatic positioning. Although many individuals with SCI remain asymptomatic to hypotension and orthostatic hypotension (OH), we recently reported reduced memory and marginally reduced attention and processing speed in hypotensive individuals with SCI compared to a normotensive cohort. Thus, we believe that treatment of overtly asymptomatic hypotension and OH in the SCI population is clinically warranted. Currently the FDA has approved only midodrine hydrochloride for the treatment of dizziness associated with OH and proof of efficacy is limited. Acetylcholinesterase inhibition for treatment of OH is a novel concept and has gained recent recognition in models of neurogenic OH (multiple system atrophy; pure autonomic failure, diabetic neuropathy). The physiological rationale of this concept is unique: acetylcholine (AcH) is the pre-ganglionic neurotransmitter of the sympathetic nervous system. Inhibition of acetylcholinesterase will limit the breakdown of AcH thereby facilitating vascular adrenergic tone and peripheral vasoconstriction. Acetylcholinesterase inhibition has been reported to be efficacious in models of both pre-ganglionic (multiple system atrophy) and post-ganglionic (pure autonomic failure, diabetic neuropathy) origin and persons with SCI reflect a model of a preganglionic disorder. In theory, if an individual has a complete autonomic lesion, acetylcholinesterase inhibition would not be expected to improve orthostatic BP because little/no neural traffic would be transmitted to the pre-synapse. However, individuals with an incomplete autonomic lesion may benefit from this class of agent. Researchers are currently investigating the orthostatic BP effects of acetylcholinesterase inhibition with pyridostigmine bromide
Sponsor: James J. Peters Veterans Affairs Medical Center

Current Primary Outcome: Systolic Blood Pressure [ Time Frame: Average systolic blood pressure over 45 minutes at 45 degrees following pyridostigmine administration compared to the average systolic blood pressure at 45 degrees during a no-drug head-up tilt maneuver. ]

Original Primary Outcome: Same as current

Current Secondary Outcome: Heart Rate [ Time Frame: Average heart rate over 45 minutes at 45 degrees following pyridostigmine administration compared to the average heart rate at 45 degrees during a no-drug head-up tilt maneuver. ]

Original Secondary Outcome: Same as current

Information By: James J. Peters Veterans Affairs Medical Center

Dates:
Date Received: May 21, 2014
Date Started: January 2011
Date Completion: December 2015
Last Updated: December 1, 2014
Last Verified: December 2014