Combination Chemotherapy Extends the Therapeutic Window to 60 Minutes After Stroke

Lyden, Patrick D.; Lonzo, Lisa; Nunez, Sonia

doi:10.1089/neu.1995.12.223

Cited by 30 publications

(12 citation statements)

References 20 publications

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“…The quantal bioassay uses a different behavioral outcome, is simpler, and is well suited to studies of the therapeutic time window 13 , 8 . We confirmed (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Direct Thrombin Inhibitor Argatroban Reduces Stroke Damage in 2 Different Models

Lyden

Pereira

Chen

et al. 2014

Stroke

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Background and Purpose We showed previously robust neuroprotection with the thrombin inhibitor argatroban, and now sought additional support for its neuroprotective potential. Methods We used behavioral and histological endpoints; rigorously blinded the study groups; extended the treatment window to 3 hours following ischemia onset; and used 2 separate models. First, 2-h filament MCAo in 64 male Sprague-Dawley rats was followed by learning and memory testing and quantitative histomporphometry. Randomly assigned treatment was 0.45mg argatroban, saline, or 0.4U thrombin. Second, we used the quantal bioassay (n=272) after 2-hour MCAo to detect the longest time delay after which therapy failed. Results Argatroban powerfully and significantly reversed learning and memory deficits due to focal ischemia compared to saline or thrombin (p<0.03, ANOVA). Argatroban was significantly (p<0.05, t-test with Bonferroni) protective when given immediately or after 1, 2, 3 but not 4 hours delay. Conclusions We obtained supportive evidence for argatroban protection of the neurovascular unit using behavioral and histological measurements at realistic therapeutic time windows.

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“…The quantal bioassay uses a different behavioral outcome, is simpler, and is well suited to studies of the therapeutic time window 13 , 8 . We confirmed (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Treatment effects were assessed using the standard quantal bioassay procedure, and TTC staining 8 . Treatment groups were compared using a t-test of the respective ED 50 s using a Bonferroni correction for multiple comparisons.…”

Section: Methodsmentioning

confidence: 99%

Direct Thrombin Inhibitor Argatroban Reduces Stroke Damage in 2 Different Models

Lyden

Pereira

Chen

et al. 2014

Stroke

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“…91,92 Administration of rt-PA increases perfusion of ischemic penumbra, preserves salvageable core tissue, and may extend the therapeutic window for neuroprotective therapy. 91,92 Co-administration of neuroprotective agents may extend the therapeutic window of rt-PA. 93 Furthermore, reperfusion with a thrombolytic permits the neuroprotective agent to better penetrate the previously ischemic region.…”

Section: Possible Answers For Future Clinical Trialsmentioning

confidence: 99%

Neuroprotection for ischemic stroke: Two decades of success and failure

Al-Khoury

Zivin

2004

Neurotherapeutics

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Summary: Alteplase (rt-PA) is the first therapy successfully developed for acute stroke therapy. The success of rt-PA spurred development of new avenues for acute stroke management. For the last two decades, a great deal of attention has been paid to neuroprotective therapies. Initial preclinical studies demonstrated numerous drugs are effective for treating acute stroke in animal models; however, subsequent clinical trials have been frustrating, and none of the agents has proven effective. The various outcomes of preclinical and clinical trials have been the subject of much discussion. In this article, we review some key neuroprotective trials and the possible reasons for their failures. By identifying the discrepancies between preclinical studies and clinical trials, we may be able to set guidelines for future effective trials.

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“…22,23 Agonists of GABA receptors are neuroprotective if administered during or after ischemia. [7][8][9]11,18,24,25 Allopregnanolone and its synthetic analogue ganaxolone are active at the GABA A receptor. 3,26,27 These neuroactive steroids have no glucocorticoid activity and have no effects on the inflammatory system.…”

Section: Discussionmentioning

confidence: 99%

Effect of Ganaxolone in a Rodent Model of Cerebral Hematoma

Lyden¹,

Shin²,

Jackson-Friedman³

et al. 2000

Stroke

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Background and Purpose-Therapy with ␥-aminobutyric acid (GABA) agonists appears to improve outcome after experimental hematoma but with unacceptable side effects. We looked to synthetic GABA agonists, or positive GABA modulators, widely developed as anticonvulsants and anxiolytics, to find compounds that may be effective. Ganaxolone is a synthetic neuroactive steroid that positively modulates GABA. We sought to determine whether ganaxolone was beneficial using a model of intracerebral hematoma. Methods-We stereotaxically injected varying doses of bacterial collagenase into the caudate nucleus of rats to induce blood-brain barrier failure and hematoma formation. Four hours later, we administered intravenously 15 or 30 mg/kg ganaxolone (nϭ23 each group), 20 mg/kg pregnanolone (nϭ21), or vehicle (nϭ30). Forty-eight hours after collagenase injection, we rated each animal using a standard rodent neurological examination. The ratings were compared with the amounts of injected collagenase using the quantal bioassay procedure. Other sets of animals were tested later for visuospatial learning. Brains were then prepared for histomorphometry, and brain volumes were estimated. Results-We found that ganaxolone 30 mg/kg significantly increased the ED 50 in the bioassay, for a potency ratio of 1.8Ϯ0.41 compared with vehicle (PϽ0.05). Ganaxolone 15 mg/kg and pregnanolone did not affect neurological outcome. Ganaxolone 30 mg/kg did not clearly improve visuospatial learning several weeks after hemorrhage. Ganaxolone exhibited a weak effect on cerebral volumes 48 hours after stroke, but 3 months after hemorrhage no such effect could be detected. Conclusions-Ganaxolone improves neurological outcome 48 hours after intracerebral hematoma but not visuospatial learning several weeks after intracerebral hematoma. Histological evidence of damage was reduced at 48 hours but not at 3 months. (Stroke. 2000;31:169-175.)

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Combination Chemotherapy Extends the Therapeutic Window to 60 Minutes After Stroke

Cited by 30 publications

References 20 publications

Direct Thrombin Inhibitor Argatroban Reduces Stroke Damage in 2 Different Models

Direct Thrombin Inhibitor Argatroban Reduces Stroke Damage in 2 Different Models

Neuroprotection for ischemic stroke: Two decades of success and failure

Effect of Ganaxolone in a Rodent Model of Cerebral Hematoma

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