A specific dopamine D1 agonist, DAS-431, for the treatment of hemispatial neglect and motor deficits following stroke.
Lead Research Organisation:
University College London
Department Name: UNLISTED
Abstract
After suffering a stroke patients often have difficulties with their thinking and in controlling their arm or leg. Our research will look at the effects of a new drug on individuals with a stroke of the right side of the brain. These patients often suffer from a condition called hemispatial neglect. They fail to be aware of large objects – even people – to their left. They also often have weakness or poor control of their left arm and leg. At the moment, there is no effective drug treatment for these problems.
The drug we will test acts on a receptor on brain cells known as the dopamine D1 receptor. In studies on monkeys, drugs that act on this receptor improve memory for spatial locations, and spatial memory is often impaired in stroke patients with hemispatial neglect. Recent investigations in stroke patients also suggest that stimulating dopamine receptors in the brain may improve control of movement.
Professor Masud Husain and Dr Nick Ward are brain doctors who have a special interest in trying to treat hemispatial neglect and motor problems after stroke. They will ask patients with these problems if they would like to take part in a test to see if a drug that acts at dopamine D1 receptors can improve their ability to look to the left or use their left arm or leg.
The doctors predict that patients who benefit most from the drug will be those who have the frontal parts of their brain intact - because the drug is likely to have its beneficial effects by stimulating dopamine receptors in this part of the brain.
If this test is successful, a trial could be organized to see how effective the treatment is in a larger group of patients.
The drug we will test acts on a receptor on brain cells known as the dopamine D1 receptor. In studies on monkeys, drugs that act on this receptor improve memory for spatial locations, and spatial memory is often impaired in stroke patients with hemispatial neglect. Recent investigations in stroke patients also suggest that stimulating dopamine receptors in the brain may improve control of movement.
Professor Masud Husain and Dr Nick Ward are brain doctors who have a special interest in trying to treat hemispatial neglect and motor problems after stroke. They will ask patients with these problems if they would like to take part in a test to see if a drug that acts at dopamine D1 receptors can improve their ability to look to the left or use their left arm or leg.
The doctors predict that patients who benefit most from the drug will be those who have the frontal parts of their brain intact - because the drug is likely to have its beneficial effects by stimulating dopamine receptors in this part of the brain.
If this test is successful, a trial could be organized to see how effective the treatment is in a larger group of patients.
Technical Summary
Patients with stroke frequently have major cognitive and motor deficits. The purpose of this research project is to assess the effects of a selective dopamine D1 receptor agonist, DAS-431, on individuals with right-hemisphere stroke. Such patients often suffer from hemispatial neglect (unawareness of objects to their left) as well as having weakness or poor control of their left limb movements.
In monkey studies DAS-431 has been shown to improve spatial working memory (SWM), a cognitive process which is often impaired in patients with hemispatial neglect, contributing to their lack of exploration of left space. Recent experiments in stroke patients also suggest dopaminergic stimulation may improve motor control. Because DAS-431 has a good safety profile and its side effects have been established in human subjects, it can now be tested in a proof-of-concept study in stroke patients.
We will use a randomization test design, assessing patients? spatial and attentional cognitive functions and their motor control prior to, during and after intervention. The study is double-blind, with placebo control, and is ideally suited for a small proof-of-concept trial to establish whether intravenous DAS-431 can ameliorate hemispatial neglect and/or motor deficits. All patients will receive the drug at some randomized point during the trial. Performance in the treatment phase will be compared to non-treatment phases, using established distribution-free permutation statistical methods.
All patients will be tested with a battery of cognitive and motor tasks, and in addition will have their stroke lesions plotted using high resolution magnetic resonance imaging. Both acute (within 1 hour) and longer-term (3 weeks) effects of intravenous DAS-431 will be evaluated. Because the critical target of DAS-431 appears to be D1 dopamine receptors in prefrontal cortex, we predict that patients with extensive prefrontal damage are least likely to respond to the compound. Patients will therefore be stratified into four groups according to the extent of their prefrontal damage.
If successful, the results of the trial can be exploited quickly, in combination with our industrial partner (DAS), to facilitate a larger scale international randomized trial. Currently, there are no established drug treatments for cognitive or motor deficits following stroke. D1 dopaminergic treatment presents an important opportunity to translate animal research into a clinical arena which has a huge unmet need.
In monkey studies DAS-431 has been shown to improve spatial working memory (SWM), a cognitive process which is often impaired in patients with hemispatial neglect, contributing to their lack of exploration of left space. Recent experiments in stroke patients also suggest dopaminergic stimulation may improve motor control. Because DAS-431 has a good safety profile and its side effects have been established in human subjects, it can now be tested in a proof-of-concept study in stroke patients.
We will use a randomization test design, assessing patients? spatial and attentional cognitive functions and their motor control prior to, during and after intervention. The study is double-blind, with placebo control, and is ideally suited for a small proof-of-concept trial to establish whether intravenous DAS-431 can ameliorate hemispatial neglect and/or motor deficits. All patients will receive the drug at some randomized point during the trial. Performance in the treatment phase will be compared to non-treatment phases, using established distribution-free permutation statistical methods.
All patients will be tested with a battery of cognitive and motor tasks, and in addition will have their stroke lesions plotted using high resolution magnetic resonance imaging. Both acute (within 1 hour) and longer-term (3 weeks) effects of intravenous DAS-431 will be evaluated. Because the critical target of DAS-431 appears to be D1 dopamine receptors in prefrontal cortex, we predict that patients with extensive prefrontal damage are least likely to respond to the compound. Patients will therefore be stratified into four groups according to the extent of their prefrontal damage.
If successful, the results of the trial can be exploited quickly, in combination with our industrial partner (DAS), to facilitate a larger scale international randomized trial. Currently, there are no established drug treatments for cognitive or motor deficits following stroke. D1 dopaminergic treatment presents an important opportunity to translate animal research into a clinical arena which has a huge unmet need.
