Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.8 (FAST)
 758 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apart from management in a specialised stroke or neurological intensive care unit, until very recently no specific therapies improved outcome after intracerebral haemorrhage (ICH). In a recent phase II trial, recombinant activated factor VII (eptacog alfa) reduced haematoma expansion, mortality, and disability when given within 4 h of ICH onset; a phase III trial (the FAST trial) is now in progress. Ventilatory support, blood-pressure reduction, intracranial-pressure monitoring, osmotherapy, fever control, seizure prophylaxis, and nutritional supplementation are the cornerstones of supportive care in intensive care units. Ventricular drainage should be considered in all stuporous or comatose patients with intraventricular haemorrhage and acute hydrocephalus. Given the lack of benefit seen in a the recent STICH trial, emergency surgical evacuation within 72 h of onset should be reserved for patients with large (>3 cm) cerebellar haemorrhages, or those with large lobar haemorrhages, substantial mass effect, and rapidly deteriorating condition.
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PMID:Treatment of intracerebral haemorrhage. 1616 35

Intracerebral hemorrhage is the least treatable form of stroke and is associated with 30% to 50% mortality rate. Early hematoma growth occurs in 18% to 38% of patients scanned within 3 hours of intracerebral hemorrhage onset, and hematoma volume is an important predictor of poor outcome. Recombinant activated factor VII, a potent initiator of hemostasis, is currently approved for the treatment of bleeding in hemophilia patients with inhibitors and has also been shown to promote hemostasis in patients with normal coagulation. A recent phase IIB randomized, double-blind, placebo-controlled, dose-ranging "proof-of-concept" trial enrolled 399 intracerebral hemorrhage patients to determine whether recombinant activated factor VII can limit ongoing bleeding and improve outcome. An approximate 50% relative reduction in hematoma growth was evident with all 3 doses that were tested (40, 80, and 160 microg/kg), which translated into an average reduction in absolute intracerebral hemorrhage volume growth of approximately 5 milliliters. More importantly, recombinant activated factor VII was associated with a 38% relative reduction in mortality and significantly improved functional outcome among survivors, despite a 5% frequency of arterial thromboembolic events (primarily ischemic stroke and myocardial infarction). A large phase III trial (the FAST trial [Factor Seven for Acute Hemorrhagic Stroke Treatment]) is now in progress to confirm these findings.
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PMID:Recombinant activated factor VII for acute intracerebral hemorrhage. 1751 Apr 50

Intracerebral hemorrhage (ICH) comprises 15% of all strokes, and carries the highest risk of mortality and poor long-term outcome. ICH has long been recognized as the least treatable form of stroke, and hematoma volume as the strongest single predictor of mortality and outcome. CT-based studies have found that early substantial hematoma expansion occurs in 18-38% of patients initially scanned within 3 h of symptom onset. This finding is associated with early neurological deterioration and an increased risk of poor outcome. Ultra-early hemostatic therapy might be beneficial in preventing hematoma growth, resulting in improved mortality and neurological function. Recombinant activated factor VII (rFVIIa) promotes local hemostasis in the presence or absence of coagulopathy at sites of vascular injury, and is a promising treatment for arresting active bleeding in ICH. The safety and feasibility of this approach was confirmed in a phase IIb randomized, double-blind, placebo-controlled, dose-ranging trial of 399 patients with non-coagulopathic ICH. Administration of rFVIIa within 4 h of ICH onset resulted in a significant reduction of hematoma expansion at 24 h, and reduced mortality and improved functional outcome at 90 days. A confirmatory phase III trial (The FAST Trial) to confirm these results will complete enrollment in the end of 2006.
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PMID:Reducing the risk of ICH enlargement. 1763 8

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.
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PMID:Advances in hemorrhagic stroke therapy: conventional and novel approaches. 1787 68

This article covers three major topics of acute stroke therapy: extension of the time window for thrombolysis with desmoteplase, decompressive surgery after malignant middle cerebral artery infarction, and the effect of hemostatic therapy with recombinant activated factor VII (rFVIIa) in patients with spontaneous primary intracerebral hemorrhage. Thrombolytic therapy with recombinant tissue or tissue-type plasminogen activator is still the only approved acute stroke therapy within a 3-h time window. Imaging-based patient selection seems to help extending this time window. After promising results of two phase II trials with the thrombolytic agent desmoteplase in an extended time window after acute ischemic stroke, the DIAS-II study was reconducted in Europe, North America, and Australia as a phase III trial. First results of the included 186 patients are shown. Surprisingly, patients treated with desmoteplase had no better outcome than placebo-treated patients, and there was increased mortality in the high-dose group. Among all stroke subtypes, space-occupying malignant middle cerebral artery is one with the poorest prognosis. Most patients die within a few days due to the development of massive brain edema, despite maximum intensive care. Decompressive hemicraniectomy represents a much more effective therapy for the treatment of local brain swelling. However, until recently this method was highly controversial. Here we present the results of the randomized trials published in 2007 and discuss their relevance for acute therapy. Hematoma growth occurs within 4 h in one third of patients who suffer from intracerebral hemorrhage. Prospective, placebo-controlled, multicenter trials have shown that intravenous application of rFVIIa reduces volume increase. We present preliminary results of the latest phase III trial (FAST: recombinant factor VIIa in acute hemorrhagic stroke), which tried to find whether the hemostatic effect will translate into clinical effect.
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PMID:[Acute stroke therapy. Current developments]. 1787 77