title: Advances in hemorrhagic stroke therapy: conventional and novel approaches.
abstract: Treatments for spontaneous intracerebral, thrombolytic-induced and intraventricular hemorrhages (IVH) are still at the preclinical or early clinical investigational stages. There has been some renewed interest in the use of surgical evacuation surgery or thrombolytics to remove hematomas, but these techniques can be used only for specific types of brain bleeding. The STICH (Surgical Trial in Intracerebral Haemorrhage) clinical trials should provide some insight into the potential for such techniques to counteract hematoma-induced damage and subsequently, morbidity and mortality. More recently, clinical trials (ATACH [Antihypertensive Treatment in Acute Cerebral Hemorrhage] and INTERACT [Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial]) have begun testing whether or not regulating blood pressure affects the well-being of hemorrhage patients, but the findings thus far have not conclusively demonstrated a positive result. More promising trials, such as the early stage CHANT (Cerebral Hemorrhagic And NXY-059 Treatment) and the late stage FAST (Factor VIIa for Acute Hemorrhagic Stroke Treatment), have addressed whether or not manipulating oxidative stress and components of the blood coagulation cascade can achieve an improved prognosis following spontaneous hemorrhages. However, CHANT was halted prematurely because although it showed that the spin trap agent NXY-059 was safe, it also demonstrated that the drug was ineffective in treating acute ischemic stroke. In addition, the recombinant activated factor VII FAST trial recently concluded with only modestly positive results. Despite a beneficial effect on the primary end point of reducing hemorrhage volume, controlling the coagulation cascade with recombinant factor VIIa did not decrease the mortality rate. Consequently, Novo Nordisk has abandoned further development of the drug for the treatment of intracerebral hemorrhaging. Even though progress in hemorrhage therapy that successfully reduces the escalating morbidity and mortality rate associated with brain bleeding is slow, perseverance and applied translational drug development will eventually be productive. The urgent need for such therapy becomes more evident in light of concerns related to uncontrolled high blood pressure in the general population, increased use of blood thinners by the elderly (e.g., warfarin) and thrombolytics by acute ischemic stroke patients, respectively. The future of drug development for hemorrhage may require a multifaceted approach, such as combining drugs with diverse mechanisms of action. Because of the substantial benefit of factor VIIa in reducing hemorrhage volume, it should be considered as a prime drug candidate included in combination therapy as an off-label use if the FAST trial proves that the risk of thromboembolic events is not increased with drug administration. Other promising drugs that may be considered in combination include uncompetitive NMDA receptor antagonists (such as memantine), antioxidants, metalloprotease inhibitors, statins and erythropoietin analogs, all of which have been shown to reduce hemorrhage and behavioral deficits in one or more animal models.
authors.affiliation: University of California San Diego, Department of Neuroscience, MTF 316, 9500 Gilman Drive, La Jolla, CA 92093-0624, USA. plapchak@ucsd.edu
authors.forename: Paul A
authors.initials: PA
authors.lastname: Lapchak
authors.forename: Dalia M
authors.initials: DM
authors.lastname: Araujo
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D000975:Antioxidants / Q000627:therapeutic use; D001557:Benzenesulfonates / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D002317:Cardiovascular Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D003029:Coagulants / Q000627:therapeutic use; D004195:Disease Models, Animal; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D004921:Erythropoietin / Q000627:therapeutic use; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D015942:Factor VIIa / Q000627:therapeutic use; D006487:Hemostasis / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D020300:Intracranial Hemorrhages / Q000097:blood / Q000150:complications* / Q000188:drug therapy / Q000503:physiopathology; D018384:Oxidative Stress / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D020521:Stroke / Q000097:blood / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D016896:Treatment Outcome
chemical_list: D000959:Antihypertensive Agents; D000975:Antioxidants; D001557:Benzenesulfonates; D002317:Cardiovascular Agents; D003029:Coagulants; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D004921:Erythropoietin; C120851:disufenton sodium; D015942:Factor VIIa