Postischemic (S)-emopamil therapy ameliorates focal ischemic brain injury in rats.

Morikawa, Eiharu; Ginsberg, Myron D.; Dietrich, W. Dalton; Duncan, Robert C.; Busto, Raul

doi:10.1161/01.str.22.3.355

Cited by 27 publications

(2 citation statements)

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“…Morikawa et al explored the post-ischemic 'therapeutic window' for (S)-emopamil; with repeated doses i.p., they showed that significant reduction of infarct volume was found with 1 h of post-occlusion administration (48% reduction, p < 0.05), with a timedependent decline in effect. 17 The addition of transvenous perfusion of verapamil through an artery to vein graft to the brain after MCAO in rodent models resulted in significant improvement in cerebral blood flow, with significant reduction in total cerebral infarct. 41 Finally, verapamil is a first-pass metabolic agent, with 90% binding to plasma proteins.…”

Section: Discussionmentioning

confidence: 99%

“…Preclinical studies evaluating calcium channel blockers for stroke neuroprotection have shown some promise. [15][16][17] Recently, our laboratory has published in vivo studies demonstrating the neuroprotective effects of coupling recanalization with IA verapamil in a mouse model of focal cortical ischemia (transient middle cerebral artery occlusion). 18 We demonstrated that, when administered IA following recanalization, verapamil was physiologically safe (heart rate and blood pressure), and it significantly reduced infarct volume and significantly improved functional outcome.…”

Section: Introductionmentioning

confidence: 99%

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Intra-arterial verapamil post-thrombectomy is feasible, safe, and neuroprotective in stroke

Fraser

Maniskas

Trout

et al. 2017

J Cereb Blood Flow Metab

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Large vessel ischemic stroke represents the most disabling subtype. While t-PA and endovascular thrombectomy can recanalize the occluded vessel, good clinical outcomes are not uniformly achieved. We propose that supplementing endovascular thrombectomy with superselective intra-arterial (IA) verapamil immediately following recanalization could be safe and effective. Verapamil, a calcium channel blocker, has been shown to be an effective IA adjunct in a pre-clinical mouse focal ischemia model. To demonstrate translational efficacy, mechanism, feasibility, and safety, we conducted a group of translational experiments. We performed in vivo IA dose-response evaluation in our animal stroke model with C57/Bl6 mice. We evaluated neuroprotective mechanism through in vitro primary cortical neuron (PCN) cultures. Finally, we performed a Phase I trial, SAVER-I, to evaluate feasibility and safety of administration in the human condition. IA verapamil has a likely plateau or inverted-U dose-response with a defined toxicity level in mice (LD 50 16-17.5 mg/kg). Verapamil significantly prevented PCN death and deleterious ischemic effects. Finally, the SAVER-I clinical trial showed no evidence that IA verapamil increased the risk of intracranial hemorrhage or other adverse effect/procedural complication in human subjects. We conclude that superselective IA verapamil administration immediately following thrombectomy is safe and feasible, and has direct, dose-response-related benefits in ischemia.

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Section: Discussionmentioning

confidence: 99%