Agents In Acute Ischemic Stroke Research Articles

Comparative efficacy and safety among different doses of tenecteplase for acute ischemic stroke: A systematic review and network meta-analysis

ObjectivesTenecteplase (TNK) is a promising alternative to alteplase (ALT) as the thrombolytic agent for acute ischemic stroke (AIS). However, its clinical outcomes in certain populations remain unclear. This study aimed to compare the efficacy and safety among different doses of TNK in AIS patients. MethodsWe searched PubMed, Scopus, Cochrane Central Register of Controlled Trials, and Embase for studies comparing at least one dose of TNK to another dose of TNK or ALT 0.90 mg/kg. We conducted Bayesian network meta-analyses to estimate the relative risks (RRs) and 95% credible intervals (CrIs) for all outcomes using ALT 0.90 mg/kg as the reference. The treatments were ranked according to their surface under the cumulative ranking (SUCRA) values. ResultsWe included 11 trials from 16 publications comprising 5423 participants. There were no significant differences between any doses of TNK and ALT for reperfusion, 3-month modified Rankin Score (mRS) 0–1 (rank 1st: TNK 0.25 mg/kg; SUCRA = 0.68), mRS 0-2 (rank 1st: TNK 0.25 mg/kg; SUCRA = 0.86), mortality (rank 1st: TNK 0.25 mg/kg; SUCRA = 0.82), intracranial hemorrhage (ICH) (rank 1st: TNK 0.25 mg/kg; SUCRA = 0.88), symptomatic ICH (sICH) (rank 1st: TNK 0.10 mg/kg; SUCRA = 0.70), and parenchymal hematoma (rank 1st: TNK 0.10 mg/kg; SUCRA = 0.68). TNK 0.40 mg/kg had a significantly higher sICH rate compared to TNK 0.25 mg/kg (RR = 2.39, 95% CrI = 1.00–7.92). Among elderly patients, TNK 0.25 mg/kg had a significantly lower rate of sICH than ALT 0.9 mg/kg (RR = 3.0 × 10-13, 95% CrI = 3.4 × 10-40–0.07). ConclusionsTNK has efficacy and safety outcomes comparable to those of ALT. TNK 0.25 mg/kg may be the optimal dose of TNK for patients with AIS.

A pilot study of a novel brain penetrant Mn(III) porphyrin-based SOD mimic on middle cerebral artery occlusion in mice

Introduction: Oxidative stress exacerbates acute ischemic stroke (AIS). Manganese Porphyrin (MnP)-based superoxide dismutase (SOD) mimics have shown therapeutic benefits for AIS. However, earlier MnP versions faced limited blood-brain barrier (BBB) penetration and hypotension. A novel SOD mimic MnP-05 is designed to overcome the limitations of previous generation structural analogs. Our study aimed to assess whether MnP-05 improves transient middle cerebral artery occlusion (tMCAO) outcomes in mice. Methods: Male and female C57BL/6J mice aged 12-14 weeks were used and data collection was aggregated. Initially, a safety study was conducted using uninjured mice to establish safe dosage levels independent of hypotension. Subsequently, pharmacokinetic (PK) analysis assessed BBB penetration of MnP-05. Finally, effcacy studies of MnP-05 were assessed following a 60-minute tMCAO. Intravenous administration of 1 mg/kg of MnP-05 occurred 10 minutes after recanalization, followed by intraperitoneal implantation of an osmotic pump delivering 5 mg/kg/day of MnP-05 for 72 hours after tMCAO. The concentration of MnP-05 was evaluated in ischemic core and contralateral normal brain by LC-MS/MS. The neurological symptoms were assessed by Garcia score and neurological deficit score (NDS) and compared at 72 hours between the control and MnP-05 groups in the effcacy study. Results: The safety study revealed that doses of 10mg/kg or less were considered safe, not causing hypotension (Fig.1). In the PK study, MnP-05 demonstrated preferential distribution to ischemic lesions compared to contralateral side (p = 0.03, Fig.2). In the effcacy study, MnP-05 group demonstrated improved neurological symptoms at 72 hours in Garcia score (p = 0.02), NDS (p = 0.006), and probability of survival (p = 0.03)(Fig.3). Conclusions: We established the safety dose of MnP-05 in tMCAO mice. It penetrates in ischemic lesions through BBB. Our findings suggest that MnP-05 is a promising therapeutic agent for AIS. None. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

507 Neuroprotective Effects of a Steroid Receptor Coactivator Stimulator in a Murine Model of Acute Ischemic Stroke with Reperfusion

INTRODUCTION: Stroke is the leading cause of adult disability and the fifth leading cause of mortality in the United States. Despite the study of many neuroprotective agents for acute ischemic stroke, none has been shown to be effective in large randomized clinical trials. Steroid receptor coactivator (SRC) is a promising class of agents since they are involved in cellular proliferation and regeneration, immune modulation, angiogenesis, antioxidant protection and are expressed in the brain. METHODS: Twenty c57bl/6 mice were randomly assigned to control or treatment groups (n = 10 mice per group). All mice underwent middle cerebral artery occlusion for 90 minutes followed by reperfusion via the intraluminal filament method. Occlusion was confirmed by laser doppler flowmetry. Intraperitoneal injections of saline (control) or 10-1 (treatment) were given 30 minutes after reperfusion. Each animal was tested using a modified Bederson’s neurological deficit scale (mNDS) and euthanized at the conclusion of the 24-hour survival period. Brain slices were stained with 2,3,5- triphenyltetrazolium chloride (TTC) to identify ischemic brain tissue. RESULTS: When compared with the control group, 10-1 treated mice showed significantly lower mNDS scores (p = 0.000336) and incidence of circling (p = 0.00256). Calculated infarct volumes, based on TTC staining, of the 10-1 treated group were significantly lower (p = 0.0009) when compared to the control group. CONCLUSIONS: We have shown that 10-1 is a promising therapeutic agent and provides substantial neuroprotection through its many multicellular processes in a rodent study. Current studies are being conducted to investigate the mechanism of 10-1 as neuroprotectant.

Geographic differences in pharmacotherapy patterns and outcomes of acute ischemic stroke in China

BackgroundVast economic and healthcare status discrepancies exist among regions in China, contributing to different treatment patterns. This study was aimed to investigate the current status of pharmacotherapy for acute ischemic stroke (AIS) and outcomes in China and explore the geographic variation in stroke care.MethodsThis study was a multicenter prospective registry study, which collected the data of patients with AIS from 80 hospitals in 46 cities in 2015–2017 across China. Poor functional outcome defined as a modified Rankin Scale score of 3–6 was assessed at 3 and 12 months. Multivariate logistic regression was used.ResultsAmong 9973 eligible patients, the number of receiving intravenous thrombolysis (IVT), antiplatelet agents, anticoagulants, statin and human urinary kallidinogenase was 429 (4.3%), 9363 (93.9%), 1063 (10.7%), 6828 (74.7%) and 5112 (51.2%), respectively. Multivariable analysis showed IVT use in northeastern was significantly more frequent than in eastern region (OR = 3.17, 95% CI, 2.53–3.99), while the antiplatelets agents use were less frequent (OR = 0.46, 95%CI: 0.38–0.57). The proportions of poor outcomes at 3 and 12 months were 20.7% and 15.8%, respectively. Multivariate analysis showed AIS patients from northeastern and central region had significantly lower risk of poor outcome at month 3 and 12 than those from eastern region (all P < 0.05).ConclusionsThere was a low IVT use and a high antiplatelet agent and statin use for AIS in China. The pharmacotherapy and prognosis of AIS had variation by geographic region.Trial registrationThis study was registered with ClinicalTrials.gov (NCT02470624).

Abstract TP290: A Pilot Study of a Novel Brain Penetrant Mn(III) Porphyrin-Based Sod Mimic on Middle Cerebral Artery Occlusion in Female and Male Mice

Introduction: Oxidative stress exacerbates acute ischemic stroke (AIS). Manganese Porphyrin (MnP)-based superoxide dismutase (SOD) mimics have shown therapeutic benefits for AIS. However, earlier MnP versions faced limited blood-brain barrier (BBB) penetration and hypotension. A novel SOD mimic MnP-05 is designed to overcome the limitations of previous generation structural analogs. Our study aimed to assess whether MnP-05 improves transient middle cerebral artery occlusion (tMCAO) outcomes in mice. Methods: Male and female C57BL/6J mice aged 12-14 weeks were used. Initially, a safety study was conducted using uninjured mice to establish safe dosage levels independent of hypotension. Subsequently, pharmacokinetic (PK) analysis assessed BBB penetration of MnP-05. Finally, efficacy studies of MnP-05 were assessed following a 45-minute tMCAO. Intravenous administration of 0.5mg/kg of MnP-05 occurred 5 minutes before recanalization, followed by intraperitoneal implantation of an osmotic pump delivering 2.5mg/kg/day of MnP-05 for 72 hours after tMCAO. The concentration of MnP-05 was evaluated in ischemic core and contralateral normal brain by LC-MS/MS. The neurological symptoms were assessed at 72 hours. Results: The safety study revealed that doses of 10mg/kg or less were considered safe (Fig.1). In the PK study, MnP-05 demonstrated preferential distribution to ischemic lesions. In the efficacy study, MnP-05 group demonstrated improved neurological outcomes, although statistical significance was not achieved (Fig.2). Conclusions: We established the safety of MnP-05 in tMCAO mice. Our findings suggest that MnP-05 is a promising therapeutic agent for AIS.

Abstract 071: Oral Contraceptive Use and Development of Acute Ischemic Stroke: A Population‐Based Retrospective Cohort Study

Introduction Existing evidence remains conflicting regarding the association between oral hormonal contraceptive (OCP) use and the risk of acute ischemic stroke (AIS). Large‐scale analyses and observational data evaluating this clinical question in recent years are scarce, despite widespread use of hormonal contraception in adult females of child‐bearing age. Modern OCP formulations contain lower doses of estrogen, the putative causative agent for AIS in this population, and underscores the need to re‐evaluate the risk initially demonstrated in older formulations containing higher levels of estrogen. Methods Hospitalizations for female patients aged 15‐50 were identified in the National Inpatient Sample (NIS) registry from 2015‐2020, excluding admissions associated with pregnancy or the postpartum period. The study exposure was use of OCPs and the primary endpoint was AIS, identified by International Classification of Diseases, Tenth Revision, Clinical Modification (ICD‐10‐CM) coding. Propensity score (PS) adjustment by inverse probability weighting (IPW) was used to mimic the effects of randomization by balancing baseline clinical characteristics associated with stroke between OCP and non‐OCP users to reduce measured confounding. In addition to age and race/ethnicity, a battery of more than forty confounding covariates representing established risk factors for AIS in the general and young population were identified (cardiovascular disease, lifestyle risk factors, congenital abnormalities, vasculopathies, hypercoagulable states, migraine with aura, among others) and balanced between OCP and non‐OCP users. Sensitivity testing was performed by evaluating stroke incidence in a sub‐group of patients without any risk factors present and by assessing a negative control (head trauma), with which an association of OCP use would not be expected. The effect size of the association between OCPs and AIS was presented as an adjusted odds ratio (aOR) with 95% confidence interval (CI), with statistical significance evaluated at p &lt; 0.001. Results PS adjustment by IPW to balance all available AIS risk factors between OCP users and non‐users yielded 23,253,209 hospitalizations, 11,654,398 (50.1%) of which were associated with OCP use. The incidence of AIS was significantly greater in OCP users compared to non‐OCP users (2.8% vs. 0.4%; aOR 7.50, 95% CI 7.43 to 7.58; p &lt; 0.001). Sub‐group analysis of hospitalizations without any stroke risk factors also demonstrated a significant association of OCP use with the development of AIS (1.3% vs. 0.1%; aOR 14.84, 95% CI 13.16 to 16.72; p &lt; 0.001) following adjustment for age and race/ethnicity. In negative control analysis, OCP use was not associated with admissions associated with head trauma (1.4% vs. 1.4%; OR 1.03, 95% CI 0.95 to 1.10; p = 0.485). Conclusion Retrospective observational data from the United States in recent years suggests an association between OCP use and AIS, independent of well‐established risk factors for stroke and despite widespread adoption of lower estrogen formulations.

Urgent need for the introduction of Tenecteplase in Pakistan: A Call to action for improved stroke and Mi Care.

Madam, Tenecteplase is a recombinant tissue plasminogen activator (tPA) that is used in many countries worldwide for reperfusion in acute ischemic stroke (AIS) and STEMI because of its longer half-life and high fibrin specificity compared to other tPAs (e.g., alteplase) and Streptokinase.1 Tenecteplase binds with fibrin-rich clots using its fibronectin finger-like and kringle-2 domains. The binding allows the protease domain to cleave the Arg/Val bond, converting plasminogen into plasmin, which breaks the fibrin matrix of the thrombus, resulting in clot dissolution. While Stroke and MI remain in the top 5 leading causes of death in Pakistan2, this highly efficient thrombolytic agent is not yet accessible in most hospitals for reperfusion in acute ischemic stroke and myocardial infarction cases. Many studies offer promising results, with tenecteplase being a better thrombolytic agent for acute ischemic stroke and STEMI than alteplase. In India, studies declare tenecteplase effective and safe in STEMI patients with clinically successful thrombolysis reported in 80.67% of patients, while intracranial hemorrhage associated with tenecteplase was only 0.39%.3 Tenecteplase is more efficient and at least as safe as alteplase for acute ischemic stroke. According to a meta-analysis involving 2031 patients, the patients given Tenecteplase showed higher recanalization rates (ARD=0.11, 95%CI) and early neurological improvement (ARD=0.10, 95% CI) compared to patients given alteplase.4 Tenecteplase also has a lower cost and a more favorable pharmacokinetic profile allowing bolus injection. Regrettably, Tenecteplase is not yet accessible in Pakistan due to unclear political and administrative factors, and border restrictions. Studies claim that only six hospitals in Pakistan currently offer intravenous thrombolytic therapy with alteplase, all being private tertiary care hospitals.5 While the world is adopting Tenecteplase instead of alteplase because of its better results, a more favourable side effects profile, and lower cost, our healthcare system is still dependent on SK for IV thrombolysis in cases of STEMI, which too is sometimes not available in many hospitals. In light of available evidence suggesting Tenecteplase as a better alternative to alteplase and Streptokinase, the health government and hospital policymakers should consider introducing tenecteplase in Pakistan as the standard care for STEMI, New Onset LBBB (Left Bundle Branch Block), Acute Ischemic Stroke, Prosthetic Valve Thrombosis, Pulmonary Embolism, and Deep Venous Thrombosis.

Abstract TMP48: Current State Of Acute Stroke Thrombolysis In The MT2020+ Caribbean Region

Introduction: Alteplase is the only FDA approved thrombolytic agent for acute ischemic stroke, tenecteplase is rapidly emerging as an alternative. While both agents are readily available worldwide, low to middle income countries have limited access to acute treatment. To our knowledge, there is no validated tool available to objectively measure access to thrombolytic agents or barriers to routine clinical use. Methods: We develop the 17-item tPA Spot Check tool to assess utilization of acute stroke thrombolysis in multiple languages. This tool was used to evaluate the current state of clinical practices in the MT2020+ Caribbean Region. Data was analyzed via SPSS. Results: The survey was validated by three international experts with an Average Content Validity Index of 1 and a Universal Agreement index of 1 across three domains: local experience, financial constraints, and barriers to utilization.Survey response rate was 64% (73/114 responses) 46 in English, 14 in Spanish and 13 in French. Fifteen out of 44 MT2020+ Caribbean countries (34%) participated: Haiti, Dominican Republic, Jamaica, Puerto Rico, St. Lucia, Bermuda, Bahamas, Cayman Islands, Trinidad and Tobago, Barbados, Dominica, Venezuela, Nicaragua, Honduras, and Guadalupe. There was limited or no access to thrombolytic agents in 40% of countries surveyed, with 13% resorting to the use of streptokinase. Among cases treated with thrombolytics, 43% of patients had to pay out of pocket before treatment provided, 36% of treatment was paid by insurance plus patients and less than 10% were covered by insurance or governmental support respectively. Among 51% of countries survey, no acute thrombolytic treatment was provided for acute stroke in 2021 calendar year. Only 1 center treated more than 100 cases per year. Majority of respondents (88%) agreed there were barriers to acute stroke thrombolysis in the region. Absence of Stroke protocol (p&lt;0.001), upfront cost of alteplase (p= 0.003) and access to CT scan (p=0.03) were independent predictors of fewer patients treated per year. Conclusion: This this survey brings light to an enormous disparity in care of stroke patients around the world, specifically in the MT2020+ Caribbean region. We create a valid tool can be used to assess local access to thrombolytic.

OUTCOME OF INTRAVENOUS THROMBOLYSIS WITH TENECTEPLASE IN ACUTE ISCHEMIC STROKE.

Tenecteplase is a modied tissue plasminogen activator and newer thrombolytic agent. It has a longer half life ,which is more brin specic, produces less systemic depletion of circulating brinogen, and is more resistant to plasminogen activator inhibitor. Because of its pharmacodynamic properties which results in rapid reperfusion and lower intracranial hemorrhages. Hence the objective is to study the efcacy of tenectaplase in acute ischemic stroke including, neurological and functional outcome at 3 months which is assessed by mRS scale and also to know the complications arising out of thrombolysis with tenectaplase. This is Methods- prospective observational study of 40 cases of acute ischemic stroke undergoing thrombolysis with tenecteplase within 4.5 hours of onset. Dose of 0.2 mg /kg of tenecteplase was used for thrombolysis and outcome was evaluated with improvement in NIHSS score at arrival , 24 hrs, 1 week and at discharge, 1 and 3 month and mRS scale at 1 and 3 months. In our study, 67.5% (27 out of 40) patients met the primary clinical efcacy outc Result- ome by achieving an improvement in NIHSS score of 4 or more points at 24 h and 67% (27out of 40 patients) met the secondary clinical efcacy outcome by having an mRS scale of 0 or 1 at 3 months. Adverse events were noted in 7 patients (17.5%) of which 4 developed ICH and 3 patients showed poor clinical outcome. ConclusionTenecteplase appears to be a safe and effective agent for acute ischemic stroke because of signicant improvement in NIHSS , low disability rates were observed in the present study

Outcomes From a Nursing-Driven Acute Stroke Care Protocol for Telehealth Encounters

IntroductionNursing care is widely recognized to be a vital element in stroke care delivery. However, no publications examining clinical education and optimal workflow practices as predictors of acute ischemic stroke care metrics exist. This study aimed to explore the impact of a nurse-led workflow to improve patient care that included telestroke encounters in the emergency department. MethodsA nonrandomized prospective pre- and postintervention unit-level feasibility study design was used to explore how implementing nurse-driven acute stroke care affects the efficiency and quality of telestroke encounters in the emergency department. Nurses and providers in the emergency department received education/training, and then the Nursing-Driven Acute Ischemic Stroke Care protocol was implemented. ResultsThere were 180 acute ischemic stroke encounters (40.3%) in the control phase and 267 (59.7%) in the postintervention phase with similar demographic characteristics. Comparing the control with intervention times directly affected by the nurse-driven protocol, there was a significant reduction in median door-to-provider times (5 [interquartile range 12] vs 2 [interquartile range 9] minutes, P < .001) and in median door-to–computed tomography scan times (9 [interquartile range 18] vs 5 [interquartile range 11] minutes, P < .001); however, the metrics potentially affected by extraneous variables outside of the nurse-driven protocol demonstrated longer median door-to-ready times (21 [interquartile range 24] vs 25 [interquartile range 25] minutes, P < .001). Door-to-specialist and door-to-needle times were not significantly different. DiscussionIn this sample, implementation of the nurse-driven acute stroke care protocol is associated with improved nurse-sensitive stroke time metrics but did not translate to faster delivery of thrombolytic agents for acute ischemic stroke, emphasizing the importance of well-outlined workflows and standardized stroke code protocols at every point in acute ischemic stroke care.

Association of ischemic stroke onset time with presenting severity, acute progression, and long-term outcome: A cohort study.

Preclinical data suggest circadian variation in ischemic stroke progression, with more active cell death and infarct growth in rodent models with inactive phase (daytime) than active phase (nighttime) stroke onset. We aimed to examine the association of stroke onset time with presenting severity, early neurological deterioration (END), and long-term functional outcome in human ischemic stroke. In a Korean nationwide multicenter observational cohort study from May 2011 to July 2020, we assessed circadian effects on initial stroke severity (National Institutes of Health Stroke Scale [NIHSS] score at admission), END, and favorable functional outcome (3-month modified Rankin Scale [mRS] score 0 to 2 versus 3 to 6). We included 17,461 consecutive patients with witnessed ischemic stroke within 6 hours of onset. Stroke onset time was divided into 2 groups (day-onset [06:00 to 18:00] versus night-onset [18:00 to 06:00]) and into 6 groups by 4-hour intervals. We used mixed-effects ordered or logistic regression models while accounting for clustering by hospitals. Mean age was 66.9 (SD 13.4) years, and 6,900 (39.5%) were women. END occurred in 2,219 (12.7%) patients. After adjusting for covariates including age, sex, previous stroke, prestroke mRS score, admission NIHSS score, hypertension, diabetes, hyperlipidemia, smoking, atrial fibrillation, prestroke antiplatelet use, prestroke statin use, revascularization, season of stroke onset, and time from onset to hospital arrival, night-onset stroke was more prone to END (adjusted incidence 14.4% versus 12.8%, p = 0.006) and had a lower likelihood of favorable outcome (adjusted odds ratio, 0.88 [95% CI, 0.79 to 0.98]; p = 0.03) compared with day-onset stroke. When stroke onset times were grouped by 4-hour intervals, a monotonic gradient in presenting NIHSS score was noted, rising from a nadir in 06:00 to 10:00 to a peak in 02:00 to 06:00. The 18:00 to 22:00 and 22:00 to 02:00 onset stroke patients were more likely to experience END than the 06:00 to 10:00 onset stroke patients. At 3 months, there was a monotonic gradient in the rate of favorable functional outcome, falling from a peak at 06:00 to 10:00 to a nadir at 22:00 to 02:00. Study limitations include the lack of information on sleep disorders and patient work/activity schedules. Night-onset strokes, compared with day-onset strokes, are associated with higher presenting neurologic severity, more frequent END, and worse 3-month functional outcome. These findings suggest that circadian time of onset is an important additional variable for inclusion in epidemiologic natural history studies and in treatment trials of neuroprotective and reperfusion agents for acute ischemic stroke.

Exosomal microRNAs as Potential Biomarkers and Therapeutic Agents for Acute Ischemic Stroke: New Expectations.

The morbidity and mortality rates of ischemic stroke (IS) are very high, and IS constitutes one of the main causes of disability and death worldwide. The pathogenesis of ischemic stroke includes excitotoxicity, calcium overload, oxygen radical injury, inflammatory reactions, necrosis/apoptosis, destruction of the blood-brain barrier (BBB), and other pathologic processes. Recent studies have shown that exosomes are critical to the pathogenesis, diagnosis, and treatment of cerebral infarctions resulting from ischemic stroke; and there is growing interest in the role of exosomes and exosomal miRNAs in the diagnosis and treatment of IS. Exosomes from central nervous system cells can be found in cerebrospinal fluid and peripheral bodily fluids, and exosomal contents have been reported to change with disease occurrence. Exosomes are small membranous extracellular vesicles (EVs), 30–150 nm in diameter, that are released from the cell membrane into the depressions that arise from the membranes of multivesicular bodies. Exosomes carry lipids, proteins, mRNAs, and microRNAs (miRNAs) and transport information to target cells. This exosomal transfer of functional mRNAs/miRNAs and proteins ultimately affects transcription and translation within recipient cells. Exosomes are EVs with a double-membrane structure that protects them from ribonucleases in the blood, allowing exosomal miRNAs to be more stable and to avoid degradation. New evidence shows that exosomes derived from neural cells, endothelial cells, and various stem cells create a fertile environment that supports the proliferation and growth of neural cells and endothelial cells, inhibits apoptosis and inflammatory responses, and promotes angiogenesis. In the present review, we discuss how circulating exosomes—and exosomal miRNAs in particular—may provide novel strategies for the early diagnosis and treatment of ischemic stroke via their potential as non-invasive biomarkers and drug carriers.

Biomarkers for Antiplatelet Therapies in Acute Ischemic Stroke: A Clinical Review.

Stroke is one of the world's leading causes of disability and death. Antiplatelet agents are administered to acute ischemic stroke patients as secondary prevention. Clopidogrel involves biotransformation by cytochrome P450 (CYP) enzymes into an active metabolite, and single nucleotide polymorphisms (SNPs) can influence the efficacy of this biotransformation. Despite the therapeutic advantages of aspirin, there is significant inter-individual heterogeneity in response to this antiplatelet drug. In this clinical review, the recent advances in the biomarkers of antiplatelet agents in acute ischemic stroke are discussed. The studies reviewed herein highlight the clinical relevance of antiplatelet resistance, pharmacotherapy of antiplatelet agents predicting drug response, strategies for identifying aspirin resistance, pharmacogenetic variants of antiplatelet agents, miRNAs, and extracellular vesicles (EVs) as biomarkers toward the personalized approach in the management of acute ischemic stroke. The precise pathways contributing to antiplatelet resistance are not very well known but are presumably multi-factorial. It is essential to understand the clinical relevance of clopidogrel and aspirin-related single nucleotide polymorphism (SNPs) as potential predictive and prognostic biomarkers. Prasugrel is a next-generation antiplatelet agent that prevents ADP-platelet activation by binding irreversibly to P2Y12 receptor. There are sporadic reports of prasugrel resistance and polymorphisms in the Platelet endothelial aggregation receptor-1 (PEAR1) that may contribute to a change in the pharmacodynamics response. Ticagrelor, a direct-acting P2Y12-receptor antagonist, is easily absorbed and partly metabolized to major AR-C124910XX metabolite (ARC). Ticagrelor's primary active metabolite, ARC124910XX (ARC), is formed via the most abundant hepatic cytochrome P450 (CYP) enzyme, CYP3A4, and CYP3A5. The integration of specific biomarkers, genotype as well as phenotype-related data in antiplatelet therapy stratification in patients with acute ischemic stroke will be of great clinical significance and could be used as a guiding tool for more effective, personalized therapy.

New ‘ase’ in the hole for treatment of acute ischemic stroke

New ‘ase’ in the hole for treatment of acute ischemic stroke

Characterization of a CholesteroNitrone (ISQ-201), a Novel Drug Candidate for the Treatment of Ischemic Stroke.

Nitrones have a well-recognized capacity as spin-traps and are considered powerful free radical scavengers, which are two important issues in hypoxia-induced oxidative stress and cell death in brain ischemia. Consequently, nitrones have been proposed as therapeutic agents in acute ischemic stroke (AIS). In this paper, we update the biological and pharmacological characterization of ISQ-201, a previously identified cholesteronitrone hybrid with antioxidant and neuroprotective activity. This study characterizes ISQ-201 as a neuroprotective agent against the hypoxia-induced ischemic injury. Transitory four-vessel occlusion and middle cerebral artery occlusion (tMCAO) were used to induce cerebral ischemia. Functional outcomes were determined using neurofunctional tests. Infarct area, neuronal death, and apoptosis induction were evaluated. In addition, ISQ-201 reactivity towards free radicals was studied in a theoretical model. ISQ-201 significantly decreased the ischemia-induced neuronal death and apoptosis, in a dose-dependent manner, showing its therapeutic effect when administered up until 6 h after post-ischemic reperfusion onset, effects that remained after 3 months from the ischemic episode. Furthermore, ISQ-201 significantly reduced infarct volume, leading to recovery of the motor function in the tMCAO model. Finally, the theoretical study confirmed the reactivity of ISQ-201 towards hydroxyl radicals. The results reported here prompted us to suggest ISQ-201 as a promising candidate for the treatment of AIS.

Safety of Glycoprotein IIb-IIIa Inhibitors Used in Stroke-Related Treatment: A Systematic Review and Meta-Analysis.

Background:Endovascular therapy and intravenous thrombolysis with recombinant tissue plasminogen activator are the 2 most recommended treatments for acute ischemic stroke (AIS). Glycoprotein (GP) IIb-IIIa inhibitors are short-acting selective reversible antiplatelet agents that emerged as promising therapeutic agents for AIS about 10 years ago. Given the unclear safety profile and application coverage of GP inhibitors, we conducted this meta-analysis to explore the same.Methods:We used GP IIb-IIIa inhibitors, intracranial hemorrhage, and mortality as the key words on Medline, Web of Science, and the Embase databases. Randomized controlled trials, prospective literatures, and retrospective studies in English published between 1990 and 2020 were screened. The outcomes were relative risk (RR) of death and 90-day intracerebral hemorrhage (ICH). We pooled the results in 2 categories and conducted a subgroup analysis stratified by different drugs. The choice of the effects model depended on the value of I 2.Results:In all, 3700 patients from 20 studies were included. No GP IIb-IIIa inhibitors were found to have a remarkable influence on the ICH rate. The RR values of symptomatic ICH for abciximab and eptifibatide were 4.26 (1.89, 9.59) and 0.17 (0.04, 0.69), respectively. Both tirofiban and abciximab could decrease the mortality rate within 90 days. Age > 70 years, National Institutes of Health Stroke Scale > 15, and overall dose > 10 mg are risk factors for ICH events with tirofiban usage. Thrombectomy combined with tirofiban was safe for arterial reocclusion prevention.Conclusions:In stroke-related treatment, administration of GP IIb-IIIa inhibitors could be safe, but care should be taken regarding drug species and doses. Abciximab can increase the risk of symptomatic intracranial hemorrhage. Tirofiban and eptifibatide can be considered safe in low doses. Suitable patients should be selected using strict criteria.

Edaravone and cyclosporine A as neuroprotective agents for acute ischemic stroke.

It is well known that acute ischemic stroke (AIS) and subsequent reperfusion produce lethal levels of reactive oxygen species (ROS) in neuronal cells, which are generated in mitochondria. Mitochondrial ROS production is a self‐amplifying process, termed “ROS‐induced ROS release”. Furthermore, the mitochondrial permeability transition pore (MPTP) is deeply involved in this process, and its opening could cause cell death. Edaravone, a free radical scavenger, is the only neuroprotective agent for AIS used in Japan. It captures and reduces excessive ROS, preventing brain damage. Cyclosporine A (CsA), an immunosuppressive agent, is a potential neuroprotective agent for AIS. It has been investigated that CsA prevents cellular death by suppressing MPTP opening. In this report, we will outline the actions of edaravone and CsA as neuroprotective agents in AIS, focusing on their relationship with ROS and MPTP.

Is Tenecteplase the Preferred Thrombolytic Agent for Acute Ischemic Stroke

Alteplase is currently the only FDA-approved thrombolytic medication for acute stroke. Tenecteplase is a bioengineered compound with greater fibrin

A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials

There is no treatment for the myelin loss in multiple sclerosis, ultimately resulting in the axonal degeneration that leads to the progressive phase of the disease. We established a multi-tiered platform for the sequential screening of drugs that could be repurposed as remyelinating agents. We screened a library of 2,000 compounds (mainly Food and Drug Administration (FDA)-approved compounds and natural products) for cellular metabolic activity on mouse oligodendrocyte precursors (OPC), identifying 42 molecules with significant stimulating effects. We then characterized the effects of these compounds on OPC proliferation and differentiation in mouse glial cultures, and on myelination and remyelination in organotypic cultures. Three molecules, edaravone, 5-methyl-7-methoxyisoflavone and lovastatin, gave positive results in all screening tiers. We validated the results by retesting independent stocks of the compounds, analyzing their purity, and performing dose-response curves. To identify the chemical features that may be modified to enhance the compounds’ activity, we tested chemical analogs and identified, for edaravone, the functional groups that may be essential for its activity. Among the selected remyelinating candidates, edaravone appears to be of strong interest, also considering that this drug has been approved as a neuroprotective agent for acute ischemic stroke and amyotrophic lateral sclerosis in Japan.

Tissue Plasminogen Activator: A Literature Review

Context: The production of thrombolytic agents started in 1930s and thrombolytic therapy for stroke began in 1958, on a case by case basis, and, in 1963, a small trial performed. Evidence Acquisition: Intravenous tissue plasminogen activator (t-PA) was recognized and approved as the thrombolytic agent for acute ischemic stroke that can improve patients’ outcome and resolve their neurological deficits. The main reason for the difficulty of stroke treatment is the narrow time window, which leads to a small proportion of eligible patients to be treated with t-PA. The cost-effectiveness and feasibility of intravenous t-PA for treatment of acute stroke in 3 - 4.5 hour time window, after symptom onset, have been confirmed in previous studies. Results: Data about thrombolytic therapy, at the national level, are scarce in Asia and developing countries, compared to developed world. Thrombolytic therapy using t-PA is used in few low-income countries, including Iran. According to estimations of Iranian stroke patients, eligible for thrombolysis therapy, only 30% of Iranian stroke patients received t-PA. Conclusions: The high cost of t-PA and lack of appropriate infrastructure are the main barriers for thrombolytic therapy, in developing countries like Iran. On the other hand, most stroke units and centers, which have the infrastructure to deliver thrombolysis, are predominantly available only in large urban areas.