Tirilazad treatment does not decrease early brain injury after transient focal ischemia in cats.

Takeshima, Reiko; Kirsch, Jeffrey R.; Koehler, Raymond C.; Traystman, Richard J.

doi:10.1161/01.str.25.3.670

Cited by 25 publications

(6 citation statements)

References 57 publications

(34 reference statements)

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“…In cats tirilazad (1.5 mg/kg i.v. plus 0.2 mg/kg/h) failed to decrease damage following transient focal ischemia [37] even when given during the occlusion, but the drug was reported to be protective in baboons [38].…”

Section: Preclinical Studies On Tirilazad In Acute Ischemic Strokementioning

confidence: 99%

Free Radical Trapping as a Therapeutic Approach to Neuroprotection in Stroke: Experimental and Clinical Studies with NXY-059 and Free Radical Scavengers

Green¹,

Ashwood²

2005

CDTCNSND

105

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There is substantial experimental evidence that free radicals are produced in the brain during ischemia, during reperfusion and during intracranial hemorrhage. Removal of pathologically produced free radicals is therefore a viable approach to neuroprotection. Four compounds with free radical scavenging activity (tirilazad, ebselen, edaravone) or free radical trapping properties (NXY-059) have been examined in experimental models of stroke and evaluated clinically as neuroprotective agents. Both experimental and clinical results are reviewed in this article. Ebselen was a modestly effective neuroprotectant in a rat transient middle cerebral artery occlusion (MCAO) model when given before the start of ischemia, but not when the insult was severe. Data from the permanent MCAO model and an embolic stroke model suggested a bell shaped dose-response curve. The weak preclinical profile may explain the lack of success in clinical trials. Preclinical data on tirilazad in animal models of acute ischemic stroke are neither comprehensive nor consistent. There was little evidence of efficacy in permanent MCAO or when the drug was given several hours post-occlusion. This may explain the negative clinical trials as these did not target patients likely to reperfuse and treatment started several hours after stroke onset. While preclinical data on subarachnoid hemorrhage demonstrated an attenuation of vasospasm the clinical data were inconsistent. There is very limited published preclinical data on edaravone but it has been approved in Japan as a neuroprotectant for the treatment of stroke. Evidence is based on a single placebo controlled trial in a relatively small number of patients. The status of possible development of edaravone outside of Japan is not known. NXY-059 has been found to be a very effective agent in transient and permanent MCAO and thromboembolic models of acute ischemic stroke. Its preclinical development has been governed by adherence with the recommendations of the Stroke Therapy Academic Industry Roundtable (STAIR) group and is now being investigated in Phase III clinical trials using a therapeutic time window and plasma concentrations that are effective in rat and primate models of stroke.

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Section: Preclinical Studies On Tirilazad In Acute Ischemic Strokementioning

confidence: 99%

Free Radical Trapping as a Therapeutic Approach to Neuroprotection in Stroke: Experimental and Clinical Studies with NXY-059 and Free Radical Scavengers

Green¹,

Ashwood²

2005

CDTCNSND

105

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“…In particular, the compound has been examined in a cat modcl of moderately severe compression injury to the lumbar spinal cord. Beginning at 44 THE NEUROSCIENTIST Lazaroids and Neurodegeneration Flg. 3.…”

Section: Tirilazad In Models Of Spinal Cord Injurymentioning

confidence: 99%

Lazaroids: Mechanisms of Action and Implications for Disorders of the CNS

Hall

1997

Neuroscientist

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Oxygen radical-induced lipid peroxidation to cerebrovascular or brain parenchymal cell membranes has been implicated as a pathophysiological mechanism in both acute and chronic neurodegenerative disorders, including brain and spinal cord trauma, ischemic and hemorrhagic stroke, Alzheimer's and Parkinson's diseases, and amyotrophic lateral sclerosis. As a result, pharmacological strategies have been aimed at antagonizing lipid peroxidative damage in a safe and effective manner. Perhaps the first successful antioxidant neuroprotective approach is high dose treatment with the glucocorticoid steroid methylprednisolone, which has been reported to be effective in improving neurological recovery after blunt spinal cord injury in animals and humans. After a determination that these effects were based upon inhibition of posttraumatic lipid peroxidative reactions rather than steroid receptor interactions, a new class of 21 -aminosteroids ("lazaroids") was discovered. The lazaroids are more effective inhibitors of lipid peroxidation and, at the same time, devoid of glucocorticoid side effect potential. One of them, tirilazad (U-74006F), was found protective in a variety of preclinical neuroprotection models and is currently the subject of Phase Ill clinical trials. Thus far, the compound has been demonstrated to significantly improve 3-month survival and neurological recovery afier subarachnoid hemorrhage in humans. Although tirilazad does penetrate the injured CNS, much of its protective activity is mediated by an action on vascular endothelium. Recently, the 21 -aminosteroids have been followed up with a newer series of non-steroidal compounds, the pyrrolopyrimidines, which possess even greater antioxidant efficacy and brain penetration that may be useful for the treatment of chronic neurodegenerative disorders. NEUROSCIENTIST 3:42-51, 1997.A major role of oxygcn radical-induced cellular injury has been strongly implicatcd in thc pathophysiology of acute CNS traumatic and ischcmic injuries (1-3) and subarachnoid hemorrhage (SAH) (4). Oxidative dcgencration has also been increasingly recognized as a player in Parkinson's discasc (5-7), Alzhcimer's disease (8,9), and motor neuron discascs likc amyotrophic lateral sclerosis (ALS) (10, 11).Proteins, nuclcic acids, and carbohydrates are all susccptiblc to oxygcn radical damage, but pcrhaps the most avid targets of oxygcn radical-induced injury arc ccll mcmbranc lipids, including cholesterol and, in particular, polyunsaturated fatty acids. The process of lipid damagc by oxygcn radicals is known as lipid pcroxidation (LP). CNS tissuc provides an especially scnsitivc target for LP reactions. One reason for this is thc high content of iron found in many brain rcgions, which varics in parallcl with thc rcgional scnsitivity to cx vivo LP (12). In addition, the brain accumulatcs iron as a function of age (13). Figurc I shows the iron-catalpcd reaction Address reprint requests to: Edward D. Hall, Ph.D.. CNS Discascs Rcscarch. Pharmacia 6 : Upjohn. Inc., hlamazoo, MI 49001.mechanisms i...

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“…Tirilazad reduced infarct size when initiated before [38] or 15 min after permanent MCA occlusion [39], whereas Xue et al [40] found a sig nificant effect of tirilazad treatm ent only if the MCA occlusion was reversible. A study showing no reduction of infarct size by tirilazad treatm ent used a low dose regimen (2.4 mg/kg during 4.5 h) in female cats subjected to 90 min o f dense ischemia with regional blood flow re duced to 2-13 ml/100 g/min in cortical regions during MCA occlusion followed by reperfusion [41], Thus collat eral perfusion at a level of 15-25 ml/100 g/min, which is considered to be critical to neuronal survival in tissue threatened by ischemia [32. 36.…”

Section: Discussionmentioning

confidence: 99%

Effect of Early Treatment with Tirilazad (U74006F) Combined with Delayed Thrombolytic Therapy in Rat Embolic Stroke

Meden¹,

Overgaard

Pedersen

et al. 1996

Cerebrovasc Dis

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Sixty-eight rats were embolized in the right carotid territory with a 200-µl suspension of white clots made from autologous blood. The purpose was to investigate the effect of early treatment with tirilazad mesylate alone and in combination with thrombolytic therapy delayed 2 h. Twenty-six rats died spontaneously before the second postoperative day, and 42 animals were killed after 48 h of survival. The brains were removed, and the infarct volumes were measured in percent of the affected hemisphere. The animals that had died spontaneously were used for an estimation of an overall treatment effect in an analysis combining infarct size and mortality. Spontaneous death occurred in: 45% of the animals in the control group, 41% in the group treated with tirilazad alone, 38% of the animals treated with recombinant tissue plasminogen activator (rt-PA) and 25% of the animals receiving combined treatment. Among the surviving animals, the median infarct volume was 47% in the control group (n = 12). Tirilazad treatment (7.5 mg/kg over 5 h) initiated 10 min after embolization (n = 10) reduced median infarct volume to 15 % (p = 0.003). Human rt-PA, 20 mg/kg, was infused intravenously during 1 h starting 2 h after embolization (n = 8). This treatment reduced median infarct volume to 31% (p = 0.22). When the two treatment regimens were combined (n= 12), the median infarct volume was reduced to 17% (p = 0.007). In the analysis combining infarct size and mortality, the infarct size among the spontaneously dead rats was set to 68%, which was the largest infarct found in these animals. Following this procedure, the median infarct volume was 63% in the control group, 38% in the group treated with tirilazad alone, 44% in the rats treated with rt-PA alone and 22% in the combined treatment group (p = 0.01, compared to the control group). In conclusion, the primary data analysis of the surviving animals showed that early treatment with tirilazad significantly reduced infarct size in this stroke model, whereas the analysis combining mortality rates and infarct volume indicated that the combination of rt-PA and tirilazad was superior to either therapy alone.

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Tirilazad treatment does not decrease early brain injury after transient focal ischemia in cats.

Cited by 25 publications

References 57 publications

Free Radical Trapping as a Therapeutic Approach to Neuroprotection in Stroke: Experimental and Clinical Studies with NXY-059 and Free Radical Scavengers

Free Radical Trapping as a Therapeutic Approach to Neuroprotection in Stroke: Experimental and Clinical Studies with NXY-059 and Free Radical Scavengers

Lazaroids: Mechanisms of Action and Implications for Disorders of the CNS

Effect of Early Treatment with Tirilazad (U74006F) Combined with Delayed Thrombolytic Therapy in Rat Embolic Stroke

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