Stroke, acute ischemic

BKCa The diversity of BKCa channels can be attributed to the assembly of pore-forming a subunit together with four different auxiliary subunits ((31 -(34). BMS-204352 has been identified as a BKCa channel opener for the treatment of acute ischemic stroke although it has also been shown as an M-channel activator. Therapeutic applications for channel openers include epilepsy, bladder overactivity, asthma, hypertension, and psychosis. Other known BKCa channel openers include NS-8, NS-1619, NS-4, and certain aminoazaindole analogs. 

Acute Ischemic Stroke An Evidence-based Approach, Edited by David M. Greer. Copyright 2007 John Wiley Sons, Inc. 

However, several important studies have shown that intravenous thrombolysis may be beneficial more than 3 hours after stroke onset, provided that only patients with a significant diffusion-perfusion mismatch are treated. In one such smdy, Ribo et al. found that patients with a significant diffusion-perfusion mismatch could be treated safely and effectively in the 3-6-hour time period. In phase II of the desmo-teplase in acute stroke (DIAS) trial, patients with diffusion-perfusion mismatch were treated with desmoteplase up to 9 hours after stroke onset, and showed better outcomes than patients given placebo, with only a minimal incidence of symptomatic hemorrhage. Similar success was achieved in the same time window by the dose escalation study of desmoteplase in acute ischemic stroke (DEDAS). ... 

NfNDS rt-PA Study Group. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N EnglJMed 1995 333 1581-1587. 

Hacke W, Albers G, Al-Rawi Y, Bogousslavsky J, Davalos A, Eliasziw M, Fischer M, Furlan A, Kaste M, Lees KR, Soehngen M, Warach S, Group DS. The Desmoteplase in Acute Ischemic Stroke Trial (DIAS) a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke 2005 36 66-73. 

Karonen JO, Vanninen RL, Liu Y, 0stergaard L, Kuikka JT, Nuutinen J, Vanninen EJ, Partanen PL, Vainio PA, Korbonen K, Perkio J, Roivainen R, Sivenius J, Aronen HJ. Combined diffusion and perfusion MRI with correlation to single-photon emission CT in acute ischemic stroke. Ischemic penumbra predicts infarct growth. Stroke 1999 30 1583-1590. 

Eurlan AJ, Eyding D, Albers GW, Al-Rawi Y, Lees KR, Rowley HA, Sachara C, Soehngen M, Warach S, Hacke W, Investigators D. Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS) evidence of safety and efficacy 3 to 9 hours after stroke onset. Stroke 2006 37 1227-1231. 

Katzan IL, Eurlan AJ, Lloyd EE, Erank JI, Harper DL, Hinchey JA, Hammel JP, Qu A, Sila CA. Use of tissue-t)fpe plasminogen activator for acute ischemic stroke the Cleveland area experience. JAMA 2000 283 1151-1158. 

O Connor RE, McGraw P, Edelsohn L. Thrombolytic therapy for acute ischemic stroke why the majority of patients remain ineligible for treatment. Ann Emerg Med 1999 33 9-14. 

Kassner A, Roberts T, Taylor K, Silver F, Mikulis D. Prediction of hemorrhage in acute ischemic stroke using permeability MR imaging. Am J Neuroradiol 2005 26 2213-2217. 

Stroke is the leading cause of major long-term disability in adults and the third leading cause of death in the United States. On average, a new stroke occurs every 45 seconds. Thrombolytic therapy with intravenous recombinant tissue-plasminogen activator (IV rt-PA) is the most effective treatment for acute ischemic stroke. In this chapter, we review the rationale for thrombolysis in acute ischemic stroke, clinical evidence supporting the use of thrombolytics, and the application of thrombolysis in practice. 

This section will review the phase III clinical trials of IV thrombolytic agents for acute ischemic stroke, organized by the type of agent and the time window from stroke onset to study drug delivery (Table 3.1). The 1995 National Institute of Neurological Disorders and Stroke (NINDS) rt-PA trial is presented first because it showed that IV rt-PA, given within 3 hours of stroke onset, reduced stroke-related disability. This trial was the basis for the United States Food and Drug Administration (FDA) approval for rt-PA for use in acute ischemic stroke. 

TABLE 3.1 Large Randomized Controlled Trials of Intravenous Thrombolysis for Acute Ischemic Stroke. 

The NINDS rt-PA smdy was divided into two parts. NINDS part I included 291 patients and NINDS part II included 333 patients. In both parts, acute ischemic stroke patients presenting within 3 hours of symptom onset were randomized to placebo versus treatment with the human rt-PA Alteplase (Activase). The dose was 0.9 mg/kg (maximum dose 90 mg), with 10% of the total dose given as a bolus and the remaining 90% infused over 60 minutes. Inclusion and exclusion criteria for both parts are listed in Table 3.2. These criteria are now the standard clinical criteria used to determine IV rt-PA eligibility in acute stroke patients. 

There have been three large randomized trials of streptokinase in acute ischemic stroke treatment, all of which were terminated early because of increased sICH and mortality in the treatment group (Table 3.1)." " " ... 

The authors concluded that campaigns to educate patients to seek treatment sooner should be major components of system-wide interventions to increase the rate of thrombolysis for acute ischemic stroke. There is some evidence that public education may help to increase the rate of rt-PA utilization by encouraging earlier presentation when stroke symptoms occur. ... 

Adams HP, Jr., Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE, 3rd. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993 24 35 1. 

Kwiatkowski TG, Libman RB, Frankel M, Tilley BC, Morgenstem LB, Lu M, Broderick JP, Lewandowski CA, Marler JR, Levine SR, Brott T. Effects of tissue plasminogen activator for acute ischemic stroke at one year. National Institute of Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator Stroke Study Group. New England Journal of Medicine. 1999 340 1781-1787. 

Clark WM, Albers GW, Madden KR Hamilton S. The rtPA (alteplase) 0- to 6-hour acute stroke trial, part a (a0276g) results of a double-bhnd, placebo-controlled, multicenter study. Thrombolytic Therapy in Acute Ischemic Stroke Study Investigators. Stroke. 2000 31 811-816. 

Larrue V, von Kummer R, del Zoppo G, Bluhmki E. Hemorrhagic transformation in acute ischemic stroke. Potential contributing factors in the European Cooperative Acute Stroke Study. Stroke. 1997 28 957-960. 

Tanne D, Gorman MJ, Bates VE, Kasner SE, Scott P, Verro P, Binder JR, Dayno JM, Schultz LR, Levine SR. Intravenous tissue plasminogen activator for acute ischemic stroke in patients aged 80 years and older The tPA stroke survey experience. Stroke. 2000 31 370-375. 

Tanne D, Kasner SE, Demchuk AM, Koren-Morag N, Hanson S, Grond M, Levine SR. Markers of increased risk of intracerebral hemorrhage after intravenous recombinant tissue plasminogen activator therapy for acute ischemic stroke in clinical practice The Multicenter rt-PA Stroke Survey. Circulation. 2002 105 1679-1685. 

Donnan GA, Davis SM, Chambers BR, Gates PC, Hankey GJ, McNeil JJ, Rosen D, Stewart-Wynne EG, Tuck RR. Streptokinase for acute ischemic stroke with relationship to time of administration Australian Streptokinase (ASK) trial study group. JAMA. 1996 276 961-966. 

Thrombolytic therapy with streptokinase in acute ischemic stroke. The Multicenter Acute Stroke Trial-Europe study group. N Engl J Med. 1996 335 145-150. 

Sherman DG, Atkinson RR Chippendale T, Levin KA, Ng K, Futrell N, Hsu CY, Levy DE. Intravenous ancrod fortreatment of acute ischemic stroke The STAT study A randomized controlled trial. Stroke Treatment with Ancrod Trial. JAMA. 2000 283 2395-2403. 

Kent DM, Price LL, Ringleb P, Hill MD, Selker HP. Sex-based differences in response to recombinant tissue plasminogen activator in acute ischemic stroke A pooled analysis of randomized clinical trials. Stroke. 2005 36 62-65. 

Kent DM, Selker HP, Ruthazer R, Bluhmki E, Hacke W. The Stroke-Thrombol3dic Predictive Instrument. A predictive instrument for intravenous thrombolysis in acute ischemic stroke. Stroke. 2006 37 2957-2962. 

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