Strategies to Extend Thrombolytic Time Window for Ischemic Stroke Treatment: An Unmet Clinical Need

Background and Objective: Stroke is a leading cause of morbidity and mortality in both developed and developing countries all over the world. The only drug for ischemic stroke approved by FDA is recombinant tissue plasminogen activator (rtPA). However, only 2-5% stroke patients receive rtPAs treatment due to its strict therapeutic time window. As ischemic stroke is a complex disease involving multiple mechanisms, medications with multi-targets may be more powerful compared with single-target drugs. Dl-3-n-Butylphthalide (NBP) is a synthetic compound based on l-3-n- Butylphthalide that is isolated from seeds of Apium graveolens. The racemic 3-n-butylphthalide (dl- NBP) was approved by Food and Drug Administration of China for the treatment of ischemic stroke in 2002. A number of clinical studies indicated that NBP not only improved the symptoms of ischemic stroke, but also contributed to the long-term recovery. The potential mechanisms of NBP for ischemic stroke treatment may target different pathophysiological processes, including anti-oxidant, antiinflammation, anti-apoptosis, anti-thrombosis, and protection of mitochondria et al. Conclusion: In this review, we have summarized the research progress of NBP for the treatment of ischemic stroke during the past two decades.

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Current Perspectives Regarding Stem Cell-based Therapy for Ischemic Stroke

Current Pharmaceutical Design ◽

10.2174/1381612824666180604111806 ◽

2018 ◽

Vol 24 (28) ◽

pp. 3332-3340 ◽

Cited By ~ 4

Author(s):

Kyeong-Ah Kwak ◽

Ho-Beom Kwon ◽

Joo Won Lee ◽

Young-Seok Park

Keyword(s):

Clinical Trials ◽

Stem Cell ◽

Ischemic Stroke ◽

Time Window ◽

Experimental Studies ◽

Cell Type ◽

Stroke Treatment ◽

Cell Based Therapy ◽

Regenerative Approach ◽

Therapeutic Time Window

Stroke is a leading cause of death and disability worldwide. Conventional treatment has a limitation of very narrow therapeutic time window and its devastating nature necessitate a novel regenerative approach. Transplanted stem cells resulted in functional recovery through multiple mechanisms including neuroprotection, neurogenesis, angiogenesis, immunomodulation, and anti-inflammatory effects. Despite the promising features shown in experimental studies, results from clinical trials are inconclusive from the perspective of efficacy. The present review presents a synopsis of stem cell research on ischemic stroke treatment according to cell type. Clinical trials to the present are briefly summarized. Finally, the hurdles and issues to be solved are discussed for clinical application.

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Abstract TP52: Endovascular Therapy in Patients Over 80 Years of Age With Acute Ischemic Stroke

Stroke ◽

10.1161/str.51.suppl_1.tp52 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Janhavi M Modak ◽

Syed Daniyal Asad ◽

Jussie Lima ◽

Amre Nouh ◽

Ilene Staff ◽

...

Keyword(s):

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Symptom Onset ◽

Time Window ◽

Extended Time ◽

Stroke Patients ◽

Stroke Outcomes ◽

Stroke Treatment ◽

Group A ◽

Group B

Introduction: Acute ischemic stroke treatment has undergone a paradigm shift, with patients being treated in the extended time window (6-24 hours post symptom onset). The purpose of this study is to assess outcomes in stroke patients above 80 years of age undergoing endovascular treatment (EVT) in the extended time window. Methods: Acute ischemic stroke patients presenting to Hartford Hospital between January 2017 to June 2019 were considered for the study. Stroke outcomes in patients above 80 years of age with anterior circulation ischemic strokes presenting in the extended time window (Group A, n=30) were compared to a younger cohort of patients below 80 years (Group B, n=31). Patients over 80 years treated in the traditional time window (within 6 hours of symptom onset) served as a second set of controls (Group C, n=40). Statistical analysis was performed with a significance level of 0.05 Results: For angiographic results, there were no statistically significant differences in terms of good outcomes (TICI 2b-3) among patients of Group A, when compared to Groups B or C (p>0.05). For the endovascular procedures, no significant differences were noted in the total fluoroscopy time (Median Group A 44.05, Group B 38.1, Group C 35.25 min), total intra-procedure time (Median Group A 144, Group B 143, Group C 126 min) or total radiation exposure (Median Group A 8308, Group B 8960, Group C 8318 uGy-m 2 ). For stroke outcomes, a good clinical outcome was defined as modified Rankin score of 0-2 at discharge. Significantly better outcomes were noted in the younger patients in Group B - 35.4%, when compared to 13.3% in Group A (p=0.03). Comparative outcomes differed in the elderly patients above 80 years, Group A -13.3% vs Group C - 25%, although not statistically significant (p=0.23). There was a significant difference in mortality in patients of Group A - 40% as compared to 12% in the younger cohort, Group B (p= 0.01). Conclusions: In the extended time window, patients above 80 years of age were noted to have a higher mortality, morbidity compared to the younger cohort of patients. No significant differences were noted in the stroke outcomes in patients above 80 years of age when comparing the traditional and the extended time window for stroke treatment.

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Lessons from Recent Advances in Ischemic Stroke Management and Targeting Kv2.1 for Neuroprotection

International Journal of Molecular Sciences ◽

10.3390/ijms21176107 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6107 ◽

Cited By ~ 1

Author(s):

Chung-Yang Yeh ◽

Anthony J. Schulien ◽

Bradley J. Molyneaux ◽

Elias Aizenman

Keyword(s):

Ischemic Stroke ◽

Time Window ◽

Stroke Therapy ◽

Stroke Management ◽

Preclinical Research ◽

Endovascular Thrombectomy ◽

Stroke Treatment ◽

Cell Death Pathway ◽

To Receive ◽

Neuroprotective Therapies

Achieving neuroprotection in ischemic stroke patients has been a multidecade medical challenge. Numerous clinical trials were discontinued in futility and many were terminated in response to deleterious treatment effects. Recently, however, several positive reports have generated the much-needed excitement surrounding stroke therapy. In this review, we describe the clinical studies that significantly expanded the time window of eligibility for patients to receive mechanical endovascular thrombectomy. We further summarize the results available thus far for nerinetide, a promising neuroprotective agent for stroke treatment. Lastly, we reflect upon aspects of these impactful trials in our own studies targeting the Kv2.1-mediated cell death pathway in neurons for neuroprotection. We argue that recent changes in the clinical landscape should be adapted by preclinical research in order to continue progressing toward the development of efficacious neuroprotective therapies for ischemic stroke.

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Abstract P875: Disparities in Delivery of Endovascular Therapy: Data From the Florida State Registry

Stroke ◽

10.1161/str.52.suppl_1.p875 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Nastajjia Krementz ◽

Kefeng Wang ◽

Carolina M Gutierrez ◽

Antonio Bustillo ◽

Nils H Mueller ◽

...

Keyword(s):

Ischemic Stroke ◽

Endovascular Therapy ◽

Treatment Time ◽

Time Window ◽

Systems Of Care ◽

Multivariable Analysis ◽

South Florida ◽

Stroke Patients ◽

Stroke Treatment ◽

High Volume Hospital

Background: Access to endovascular therapy (EVT) should be equitable to all eligible ischemic stroke patients presenting within the treatment time window. In the Florida Stroke Registry (FSR) we sought to determine sex, race/ethnic, hospital and regional disparities in the delivery of EVT. Methods: From January 2010 to January 2020, a total of 99,088 ischemic stroke cases within 24 hours of symptom onset were enrolled. Multivariable logistic regression with generalized estimating equations evaluated independent predictors of EVT utilization. Results: A total of 7,812 patients received EVT (51.2% female, mean age 71.3 ± SD 14.6 years, 61.4% white, 17.4% black, 21.2% Hispanic). Compared to those not treated, EVT treated patients were more likely Hispanic (21.2% vs. 14.6%), arrived earlier to the hospital (median 120 min (IQR 292) vs. 170 min (IQR 446)), via EMS (94% vs. 66%), with more severe strokes (median NIHSS 15 (IQR11) vs. 5 (IQR 9)), to large hospitals (≥ 680 beds) (73.4% vs. 47.7%), in South Florida (50.8% vs. 38.2%). In multivariable analysis, female sex (OR 1.05, 95% CI 1-1.11), atrial fibrillation (OR 1.57, 95% CI 1.45-1.7), higher NIHSS (> 6) (OR 6.19, 95% CI 5.11-7.51) and presenting to a high-volume hospital (OR 3.47, 95% CI 2.25-5.36) positively predicted EVT utilization, whereas older age (>80 years) (OR 0.88, 95% CI 0.80-0.96), and black race (vs. white OR 0.87, 95% CI 0.76-1), were independently associated with lower use of EVT. Conclusions: In this large state-wide registry study, we found significant race-ethic and geographical disparities in delivery of EVT. Systems of care should address disparities in stroke treatment to improve access to EVT for all eligible stroke patients.

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The Role of the ACE2/MasR Axis in Ischemic Stroke: New Insights for Therapy

Biomedicines ◽

10.3390/biomedicines9111667 ◽

2021 ◽

Vol 9 (11) ◽

pp. 1667

Author(s):

Mansoureh Barzegar ◽

Karen Y. Stokes ◽

Oleg Chernyshev ◽

Roger E. Kelley ◽

Jonathan S. Alexander

Keyword(s):

Ischemic Stroke ◽

Time Window ◽

Renin Angiotensin System ◽

Experimental Stroke ◽

Stroke Treatment ◽

Angiotensin Converting Enzyme 2 ◽

Thrombolytic Agents ◽

Approved Drugs ◽

Fda Approved Drugs

Ischemic stroke remains the leading cause of neurologically based morbidity and mortality. Current stroke treatment is limited to two classes of FDA-approved drugs: thrombolytic agents (tissue plasminogen activator (tPA)) and antithrombotic agents (aspirin and heparin), which have a narrow time-window (<4.5 h) for administration after onset of stroke symptoms. While thrombolytic agents restore perfusion, they carry serious risks for hemorrhage, and do not influence damage responses during reperfusion. Consequently, stroke therapies that can suppress deleterious effects of ischemic injury are desperately needed. Angiotensin converting enzyme-2 (ACE2) has been recently suggested to beneficially influence experimental stroke outcomes by converting the vasoconstrictor Ang II into the vasodilator Ang 1–7. In this review, we extensively discuss the protective functions of ACE2-Ang (1–7)-MasR axis of renin angiotensin system (RAS) in ischemic stroke.

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Lessons from Recent Advances in Ischemic Stroke Management and Targeting Kv2.1 for Neuroprotection

10.20944/preprints202008.0094.v1 ◽

2020 ◽

Author(s):

Chung-Yang Yeh ◽

Anthony Schulien ◽

Bradley Molyneaux ◽

Elias Aizenman

Keyword(s):

Ischemic Stroke ◽

Time Window ◽

Stroke Therapy ◽

Stroke Management ◽

Preclinical Research ◽

Endovascular Thrombectomy ◽

Stroke Treatment ◽

Cell Death Pathway ◽

To Receive ◽

Neuroprotective Therapies

Achieving neuroprotection in ischemic stroke patients has been a multi-decade medical challenge. Numerous clinical trials were discontinued in futility and many were terminated in response to deleterious treatment effects. Recently however, several positive reports have generated the much-needed excitement surrounding stroke therapy. In this review, we describe the clinical studies that significantly expanded the time window of eligibility for patients to receive mechanical endovascular thrombectomy. We summarize the results available thus far for nerinetide, which can be considered the most promising neuroprotective agent yet for stroke treatment. Lastly, we reflect upon aspects of these successful trials in our own studies targeting the Kv2.1-mediated cell death pathway in neurons for neuroprotection. We propose that recent changes in the clinical landscape must be adapted by preclinical research in order to continue progressing toward the development of efficacious neuroprotective therapies for ischemic stroke.

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Classification and Characteristics of Mesenchymal Stem Cells and Its Potential Therapeutic Mechanisms and Applications against Ischemic Stroke

Stem Cells International ◽

10.1155/2021/2602871 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Pian Gong ◽

Wei Zhang ◽

Yan He ◽

Jianfeng Wang ◽

Song Li ◽

...

Keyword(s):

Ischemic Stroke ◽

Time Window ◽

Intravenous Thrombolysis ◽

Cell Types ◽

Future Perspective ◽

Significant Advance ◽

Cerebral Disease ◽

Stroke Treatment ◽

Therapeutic Mechanisms ◽

Transplantation Therapy

Ischemic stroke is a serious cerebral disease that often induces death and long-term disability. As a currently available therapy for recanalization after ischemic stroke, thrombolysis, including intravenous thrombolysis and endovascular therapy, still cannot be applicable to all patients due to the narrow time window. Mesenchymal stem cell (MSC) transplantation therapy, which can trigger neuronal regeneration and repair, has been considered as a significant advance in treatment of ischemic stroke. MSC transplantation therapy has exhibited its potential to improve the neurological function in ischemic stroke. Our review describes the current progress and future perspective of MSC transplantation therapy in ischemic stroke treatment, including cell types, transplantation approaches, therapeutic mechanisms, and preliminary clinical trials of MSC transplantation, for providing us an update role of MSC transplantation in ischemic stroke treatment.

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Endovascular treatment of acute ischemic stroke

Journal of Neurosciences in Rural Practice ◽

10.4103/0976-3147.118787 ◽

2013 ◽

Vol 04 (03) ◽

pp. 298-303 ◽

Cited By ~ 10

Author(s):

Paramdeep Singh ◽

Rupinderjeet Kaur ◽

Amarpreet Kaur

Keyword(s):

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Standard Treatment ◽

Time Window ◽

High Rate ◽

Endovascular Thrombectomy ◽

Stroke Treatment ◽

Important Approach ◽

Stent Retrievers ◽

Retrievable Stent

ABSTRACTEarly recanalization of the occluded artery leads to better clinical outcomes in patients with acute ischemic stroke (AIS) through protection of the time-sensitive penumbra. Intravenous administration of pharmacologic thrombolytic agents has been a standard treatment for AIS. To get better rates of recanalization, enhance the time window, and diminish the possibility of intracranial hemorrhage, endovascular thrombectomy was launched, with first authorization of the Merci clot retriever, a corkscrew-like apparatus, followed by approval of the Penumbra thromboaspiration system. Both devices lead to a high rate of recanalization. On the other hand, time to recanalization was on an average of 45 minutes, with most of the patients attaining only partial recanalization. More lately, retrievable stents have shown promise in decreasing the time to recanalization, and attaining a superior rate of complete clot resolution. The retrievable stent can be released within the clot to engage it within the struts of the stent, and afterwards it is taken back by pulling it under flow arrest. Neurointerventional techniques have a persistently ever-increasing and stimulating role in the management of AIS, as indicated by the advent of several important techniques. Stent retrievers have the capability to be ascertained as the most important approach to endovascular stroke treatment.

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Abstract 159: Treatment with Intravenous Tissue Plasminogen Activator in the “Golden Hour” in the National US Get With The Guidelines-Stroke Population

Stroke ◽

10.1161/str.46.suppl_1.159 ◽

2015 ◽

Vol 46 (suppl_1) ◽

Author(s):

Jeffrey L Saver ◽

Gregg C Fonarow ◽

Eric E Smith ◽

Mathew J Reeves ◽

Digvijaya Navalkele ◽

...

Keyword(s):

Ischemic Stroke ◽

Plasminogen Activator ◽

Tissue Plasminogen Activator ◽

Time Window ◽

Systems Of Care ◽

Stroke Treatment ◽

Golden Hour ◽

Intravenous Tissue Plasminogen Activator ◽

Tissue Plasminogen ◽

Independent Ambulation

Background: Innovations in prehospital and Emergency Department systems of care increasingly enable IV tissue plasminogen activator (tPA) delivery in the first 60 minutes after onset, a time window not tested in placebo-controlled clinical trials. We sought to characterize efficacy and safety outcomes when tPA is delivered in the “golden hour.” Methods: We analyzed 65,384 acute ischemic stroke patients treated with tPA within 4.5 hours of symptom onset in 1456 hospitals participating in GWTG-Stroke from Jan 2009 to Sept 2013. Multivariable logistic regression modeling was employed to evaluate the independent impact of treatment within 60 minutes of onset on outcome. Results: 878 patients (1.3%) received lytic therapy within 60 minutes of onset, versus 6490 (9.9%) in 61-90m, 46,457 (71.1%) in 91-180m, and 11,559 (17.7%) in 181-270m. Independent patient-level factors associated with treatment in the golden hour were older age (aOR 1.15 per 5 years over age 65), higher NIHSS (aOR, 1.04 per scale point), non-EMS arrival (aOR 1.59), and arrival during on hours (aOR 1.61). Hospital level predictors were higher tPA volume (aOR 1.08 per 5 cases), non-PSC (aOR 1.27), and Western region (aOR 1.38 vs Northeast). Compared with the 61-270m window, treatment within 0-60m was associated with increased independent ambulation at d/c, aOR 1.22 (95% CI 1.03-1.45); discharge to home, aOR 1.25 (1.07-1.45); and being disability-free at d/c, aOR 1.72 (95% CI 1.21-2.46, mRS 0-1). No differences were noted in in-hospital mortality or SICH. Considering all discharge mRS transitions, golden hour treatment showed greatest impact at mRS 0-1 vs 2-6 (Figure). Conclusions: Ischemic stroke treatment with IV tPA in the golden hour is associated with more frequent independent ambulation at discharge, discharge to home, and, especially, being disability free at discharge. These findings support intensive efforts, including Target: Stroke and prehospital thrombolysis, to speed treatment initiation.

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