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Sponsors and Collaborators: |
Vanderbilt University National Institutes of Health (NIH) |
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Information provided by: | Vanderbilt University |
ClinicalTrials.gov Identifier: | NCT00585559 |
The objective of this study is to determine whether acetaminophen (APAP), N-acetylcysteine (NAC), and APAP in combination with NAC will inhibit lipid peroxidation in aneurysmal subarachnoid hemorrhage (aSAH), utilizing F2-IsoPs as biomarkers for lipid peroxidation.
Condition | Intervention |
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Aneurysmal Subarachnoid Hemorrhage Cerebral Vasospasm |
Drug: Placebos for acetaminophen and N-acetylcysteine Drug: APAP 1 gm every 6 hours and N-acetylcysteine placebo Drug: NAC IV infusion at 0.5 gm hourly and APAP placebo Drug: APAP 1 gm q6 hours, plus NAC IV infusion at 0.5 gm hourly Drug: APAP 1.5 gm q6 hours, plus NAC IV infusion at 0.5 gm hourly |
Study Type: | Interventional |
Study Design: | Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Factorial Assignment, Safety/Efficacy Study |
Official Title: | Inhibition of Lipid Peroxidation and Cerebral Vasospasm by an Acetaminophen-Based Regimen in Patients With Aneurysmal Subarachnoid Hemorrhage |
Estimated Enrollment: | 120 |
Study Start Date: | April 2007 |
Estimated Study Completion Date: | September 2009 |
Estimated Primary Completion Date: | September 2009 (Final data collection date for primary outcome measure) |
Arms | Assigned Interventions |
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1: Placebo Comparator
Placebos for acetaminophen and N-acetylcysteine
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Drug: Placebos for acetaminophen and N-acetylcysteine
Placebos for acetaminophen and N-acetylcysteine
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2: Active Comparator
Acetaminophen 1 gm every 6 hours and N-acetylcysteine placebo
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Drug: APAP 1 gm every 6 hours and N-acetylcysteine placebo
Acetaminophen 1 gm every 6 hours and N-acetylcysteine placebo
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3: Active Comparator
N-acetylcysteine IV infusion at 0.5 gm hourly and acetaminophen placebo
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Drug: NAC IV infusion at 0.5 gm hourly and APAP placebo
N-acetylcysteine IV infusion at 0.5 gm hourly and acetaminophen placebo
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4: Active Comparator
Acetaminophen 1 gm every 6 hours, plus N-acetylcysteine IV infusion at 0.5 gm hourly
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Drug: APAP 1 gm q6 hours, plus NAC IV infusion at 0.5 gm hourly
Acetaminophen 1 gm every 6 hours, plus N-acetylcysteine IV infusion at 0.5 gm hourly
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5: Active Comparator
Acetaminophen 1.5 gm every 6 hours, plus N-acetylcysteine IV infusion at 0.5 gm hourly
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Drug: APAP 1.5 gm q6 hours, plus NAC IV infusion at 0.5 gm hourly
Acetaminophen 1.5 gm every 6 hours, plus N-acetylcysteine IV infusion at 0.5 gm hourly
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Aneurysmal subarachnoid hemorrhage (aSAH) is an often devastating form of stroke with high morbidity and mortality despite advances in surgical management. Approximately 30,000 patients annually suffer aSAH in the U.S. For patients who survive the initial subarachnoid hemorrhage, delayed cerebral vasospasm occurring from days 4-14 is the greatest cause of neurological disability and death. A growing body of evidence incriminates hemoprotein-catalyzed lipid peroxidation as the mediator of the vasospasm.
Hemoglobin released from lysed red cells in the subarachnoid space becomes oxidized, in which state it acts as a pseudoperoxidase and generates the protein radicals that induce lipid peroxidation. F2-isoprostanes formed by this lipid peroxidation are highly potent constrictors of cerebral arterioles. We have demonstrated a more than 5 fold mean increase in F2-isoprostanes in the cerebrospinal fluid of patients with aSAH; this increase is maximal at the time of delayed vasospasm, and the level of increase is a function of the severity of the aSAH. We hypothesize that such vasoconstrictors are major contributors to the vasospasm produced by the hemoproteins, hemoglobin and myoglobin, in diseases in which they are released from their cellular confines.
We have discovered that acetaminophen (APAP) is a potent inhibitor of hemoprotein-catalyzed lipid peroxidation with an IC50 for hemoglobin of 15 uM, which is in the range of plasma levels resulting from therapeutic doses of the drug in humans. Acetaminophen acts by reducing the ferryl-oxo radical form of the heme, and thereby prevents formation of the hemoprotein radical that initiates lipid peroxidation. To assess proof of concept in vivo, we determined the effect of acetaminophen in a rat model of rhabdomyolysis in which renal failure results from intense vasospasm. Acetaminophen blocked lipid peroxidation in this model, and prevented the renal failure with a dose that produced plasma levels in the therapeutic range for humans.
We also have demonstrated that N-acetylcysteine (NAC) will inhibit hemoprotein-catalyzed lipid peroxidation. Moreover, NAC administration increases the levels of glutathione in vivo, and glutathione is a co-substrate for the glutathione peroxidases that can reduce the levels of peroxides in the environment of the aSAH . This is important as acetaminophen is most potent in inhibiting hemoprotein-catalyzed lipid peroxidation when peroxide concentrations are low. This concerted evidence is the basis for a hypothesis that NAC will augment the efficacy of acetaminophen as an inhibitor of hemoprotein-catalyzed lipid peroxidation in aSAH.
These finding provide the rationale for a pilot study seeking proof of the concept that acetaminophen-based regimens can inhibit lipid peroxidation in patients with subarachnoid hemorrhage. Lipid peroxidation will be determined by analysis of F2-isoprostanes in cerebrospinal fluid. If such inhibition is seen, that then would provide a basis for a larger multi-center investigation to assess the effect on clinical endpoints.
This pilot study will determine whether APAP, NAC, and APAP in combination with NAC will inhibit lipid peroxidation in aneurysmal subarachnoid hemorrhage.
Ages Eligible for Study: | 20 Years and older |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Exclusion Criteria:
Responsible Party: | National Institute of Health ( Robert A. Mericle, MD ) |
Study ID Numbers: | NIHGN15431, VUMCIRB060556 |
Study First Received: | December 26, 2007 |
Last Updated: | December 26, 2007 |
ClinicalTrials.gov Identifier: | NCT00585559 |
Health Authority: | United States: Food and Drug Administration |
Lipid Peroxidation N-Acetylcysteine Acetaminophen Vasospasm |
Vascular Diseases Subarachnoid Hemorrhage Acetylcysteine Central Nervous System Diseases Intracranial Hemorrhages Brain Diseases |
Hemorrhage Cerebrovascular Disorders Acetaminophen N-monoacetylcystine Vasospasm, Intracranial |
Anti-Infective Agents Respiratory System Agents Antioxidants Molecular Mechanisms of Pharmacological Action Nervous System Diseases Physiological Effects of Drugs Protective Agents Antiviral Agents Pharmacologic Actions Pathologic Processes |
Analgesics, Non-Narcotic Sensory System Agents Therapeutic Uses Expectorants Free Radical Scavengers Cardiovascular Diseases Analgesics Peripheral Nervous System Agents Central Nervous System Agents Antidotes |