Study of Stroke Related Edema Treatments
| Status: | Not yet recruiting |
|---|---|
| Conditions: | Cardiology, Neurology |
| Therapuetic Areas: | Cardiology / Vascular Diseases, Neurology |
| Healthy: | No |
| Age Range: | 18 - 80 |
| Updated: | 9/12/2015 |
| Start Date: | August 2015 |
| End Date: | December 2016 |
| Contact: | Vishnumurthy Shushuthra Hedna, MD |
| Email: | v.hedna@neurology.ufl.edu |
| Phone: | 352-273-5550 |
Treatment of Brain Edema and Herniation Secondary to Ischemic or Hemorrhagic Stroke
Stroke remains the fourth leading cause of death in the United States (second worldwide) and
a leading cause of long-term disability, resulting in total direct and indirect costs of
approximately $73.7 billion annually. The failure of novel therapies in clinical trials
demonstrates that the complex neural response to stroke must be targeted at multiple levels
to improve patient outcomes. Despite significant improvements in stroke treatment and
management, 1 year survival rate among stroke patients aged 65 years or more is around 25%,
and 5- year survival rate amounts to approximately 50%. The highest chances of death are
within 30 days of stroke. Mortality increases due to worsening brain dysfunction, elevated
intracranial pressure (ICP), and other comorbid conditions.
Treatments aimed at reducing post-stroke cytotoxic edema may reduce the risk for development
of malignant stroke and mortality. Current treatments such as osmo-therapy and
hemicraniectomy have substantial limitations, and mortality remains high, despite these
measures outcomes remain unsatisfactory. There is a great need for alternative medical
approaches which are safe, predictable, and help to ameliorate post stroke edema.
a leading cause of long-term disability, resulting in total direct and indirect costs of
approximately $73.7 billion annually. The failure of novel therapies in clinical trials
demonstrates that the complex neural response to stroke must be targeted at multiple levels
to improve patient outcomes. Despite significant improvements in stroke treatment and
management, 1 year survival rate among stroke patients aged 65 years or more is around 25%,
and 5- year survival rate amounts to approximately 50%. The highest chances of death are
within 30 days of stroke. Mortality increases due to worsening brain dysfunction, elevated
intracranial pressure (ICP), and other comorbid conditions.
Treatments aimed at reducing post-stroke cytotoxic edema may reduce the risk for development
of malignant stroke and mortality. Current treatments such as osmo-therapy and
hemicraniectomy have substantial limitations, and mortality remains high, despite these
measures outcomes remain unsatisfactory. There is a great need for alternative medical
approaches which are safe, predictable, and help to ameliorate post stroke edema.
Previous work has demonstrated the pathophysiological role of arginine-vasopressin (AVP) in
ischemic stroke. The mechanism of action of AVP is by 3 receptor subtypes: V1a, V1b and V2
expressed in brain, pituitary gland, myocardium, vasculature and kidneys. The role of the
vasopressin receptors V1a and or V2 subtype in cerebral edema formation after ischemic
stroke remains controversial. The V1a receptor antagonism causes platelet inhibition,
aquaporin-4 up regulation; reduce infarct size and vasodilation. V1 antagonists has also
been shown to prevent ischemia-induced cerebral edema development, suggesting that the V1
vasopressin receptor is important in water regulation in brain cells. Another study
indicated that the vasopressin receptor V1 is involved in the pathogenesis of secondary
brain damage after focal cerebral ischemia. Recently, few studies have demonstrated that a
V2 receptor antagonist (OPC-31260), may be one of the effective drugs for the early
treatment of cytotoxic edema and brain injury. Treatment of OPC-31260 ameliorated cerebral
neurological deficit in transgenic (GET-1) mice after water intoxication. Treatment of
OPC-31260 also significantly abolished water accumulation and down regulated Aquaporin-4
(AQP-4) expression level in GET-1 mice after water intoxication. The intensity of AQP-4
staining was almost comparable with that of the controls without water intoxication. It was
also shown that OPC-31260 at doses of 10 to 30 mg/kg produced a dose-dependent inhibition of
subarachnoid hemorrhage-induced cerebral edema formation, accompanied by an increase in
urinary volume and decrease in urine osmolality without a significant alteration of urine
electrolytes. OPC-31260 is also effective in treating water retention diseases, such as
hyponatremia caused by inappropriate antidiuretic hormone secretion, congestive heart
failure, and liver cirrhosis. V2 receptor antagonism will also help in abolishing water
accumulation, decreased Glial Fibrillary Acidic Protein (GFAP) in astrocytes and most
importantly causes renal tubule-selective diuretic effect called aquaresis (electrolyte
sparing diuresis), which may have additional benefit in the reduction of cerebral edema.
This combined approach of V1a and V2 AVP receptor antagonism will lead to attenuation of
ischemia related cerebral edema and infarct volume by modulating ischemia-evoked AQP-4
expression. This effect should help behavior and mortality which in turn will improve
outcome in stroke patients. The purpose of this project is to test the effect of the mixed
V1a and V2 receptor blockade on ischemic or hemorrhagic stroke outcome.
In summary, the investigators are using the approach of mixed vasopressin antagonism on post
stroke edema, infarct volume and outcome. This research will lead to a greater understanding
of the roles and interactions of the different AVP receptors and pathophysiology of post
stroke cytotoxic edema. New information on the effects of mixed blockade of V1a and V2
receptors on the prevention of cytotoxic edema post stroke will be revealed.
ischemic stroke. The mechanism of action of AVP is by 3 receptor subtypes: V1a, V1b and V2
expressed in brain, pituitary gland, myocardium, vasculature and kidneys. The role of the
vasopressin receptors V1a and or V2 subtype in cerebral edema formation after ischemic
stroke remains controversial. The V1a receptor antagonism causes platelet inhibition,
aquaporin-4 up regulation; reduce infarct size and vasodilation. V1 antagonists has also
been shown to prevent ischemia-induced cerebral edema development, suggesting that the V1
vasopressin receptor is important in water regulation in brain cells. Another study
indicated that the vasopressin receptor V1 is involved in the pathogenesis of secondary
brain damage after focal cerebral ischemia. Recently, few studies have demonstrated that a
V2 receptor antagonist (OPC-31260), may be one of the effective drugs for the early
treatment of cytotoxic edema and brain injury. Treatment of OPC-31260 ameliorated cerebral
neurological deficit in transgenic (GET-1) mice after water intoxication. Treatment of
OPC-31260 also significantly abolished water accumulation and down regulated Aquaporin-4
(AQP-4) expression level in GET-1 mice after water intoxication. The intensity of AQP-4
staining was almost comparable with that of the controls without water intoxication. It was
also shown that OPC-31260 at doses of 10 to 30 mg/kg produced a dose-dependent inhibition of
subarachnoid hemorrhage-induced cerebral edema formation, accompanied by an increase in
urinary volume and decrease in urine osmolality without a significant alteration of urine
electrolytes. OPC-31260 is also effective in treating water retention diseases, such as
hyponatremia caused by inappropriate antidiuretic hormone secretion, congestive heart
failure, and liver cirrhosis. V2 receptor antagonism will also help in abolishing water
accumulation, decreased Glial Fibrillary Acidic Protein (GFAP) in astrocytes and most
importantly causes renal tubule-selective diuretic effect called aquaresis (electrolyte
sparing diuresis), which may have additional benefit in the reduction of cerebral edema.
This combined approach of V1a and V2 AVP receptor antagonism will lead to attenuation of
ischemia related cerebral edema and infarct volume by modulating ischemia-evoked AQP-4
expression. This effect should help behavior and mortality which in turn will improve
outcome in stroke patients. The purpose of this project is to test the effect of the mixed
V1a and V2 receptor blockade on ischemic or hemorrhagic stroke outcome.
In summary, the investigators are using the approach of mixed vasopressin antagonism on post
stroke edema, infarct volume and outcome. This research will lead to a greater understanding
of the roles and interactions of the different AVP receptors and pathophysiology of post
stroke cytotoxic edema. New information on the effects of mixed blockade of V1a and V2
receptors on the prevention of cytotoxic edema post stroke will be revealed.
Inclusion Criteria:
- Subjects with age ≥18 years and ≤80 years at the time of screening.
- Hemorrhagic stroke or large vessel ischemic stroke patients diagnosed by MRI or CT
scan of Head.
- Subjects who have presented to hospital within 24 hours of symptom onset.
- The subject or his/ her legal representative is willing to undergo informed consent
process prior to enrollment into this study.
Exclusion Criteria:
- Subject with age < 18 years and >80 years at the time of screening.
- Subjects with absence of stroke by imaging of brain by CT scan or MRI.
- Lacunar stroke or small vessel stroke.
- Time of symptom onset cannot be determined.
- Subjects with renal or hepatic failure.
- Subjects with hypovolemia or hypotension as determined by the study team.
- Subjects with hypernatremia.
- Subject who is pregnant or lactating.
- Subject is already participating in other investigational clinical trial.
- The subject or legal representative is unable to provide informed consent.
- The subject is medically unstable to participate in the trial as determined by the
principal investigator.
- The subject has any end stage medical condition as determined by the principal
investigator.
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