Tirilazad Mesylate in Acute Ischemic Stroke

doi:10.1161/01.str.31.9.2257

Cited by 78 publications

(8 citation statements)

References 49 publications

(34 reference statements)

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“…A second trial, using higher doses (12-15 mg/kg/day) and given within 4 h from symptom onset [159], was stopped prematurely due to safety concerns raised by TESS II, a parallel study running in Europe. A meta-analysis of trials with tirilazad concluded that the drug actually increases death and disability after ischemic stroke [160]. 4.…”

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confidence: 99%

Oxidative Stress in Ischemia/Reperfusion Injuries following Acute Ischemic Stroke

Jurcău

Ardelean

2022

Biomedicines

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Recanalization therapy is increasingly used in the treatment of acute ischemic stroke. However, in about one third of these patients, recanalization is followed by ischemia/reperfusion injuries, and clinically to worsening of the neurological status. Much research has focused on unraveling the involved mechanisms in order to prevent or efficiently treat these injuries. What we know so far is that oxidative stress and mitochondrial dysfunction are significantly involved in the pathogenesis of ischemia/reperfusion injury. However, despite promising results obtained in experimental research, clinical studies trying to interfere with the oxidative pathways have mostly failed. The current article discusses the main mechanisms leading to ischemia/reperfusion injuries, such as mitochondrial dysfunction, excitotoxicity, and oxidative stress, and reviews the clinical trials with antioxidant molecules highlighting recent developments and future strategies.

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confidence: 99%

Oxidative Stress in Ischemia/Reperfusion Injuries following Acute Ischemic Stroke

Jurcău

Ardelean

2022

Biomedicines

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“…These lessons learned were fundamental in illuminating the therapeutic potential lying within microbiome research such as the use of microbial bio-active metabolites in the treatment of neurological diseases. However, the overwhelming amount of rodent-based data could not be directly translated from bench to bedside practice (Fisher et al, 1996;Mestas and Hughes, 2004;von Herrath and Nepom, 2005;Suntharalingam et al, 2006;Payne and Crooks, 2007;Seok et al, 2013;Shay et al, 2013;Garner, 2014;Hay et al, 2014;Mak et al, 2014;Wong et al, 2019;Pound and Rebecca, 2020) as we have demonstrated for AD (Zahs and Ashe, 2010;Cummings et al, 2014) and stroke (Saxena et al, 1999;Bath et al, 2000;Davis et al, 2000;Enlimomab Acute Stroke Trial Investigators, 2001;Horn and Limburg, 2001;Gertz et al, 2006;O'Collins et al, 2006;Shuaib et al, 2007;Nave et al, 2019;Pound and Rebecca, 2020). This raises the question of how the scientific community could optimize translational research models to better reflect human physiology in health and diseases.…”

Section: Discussionmentioning

confidence: 88%

“…Indeed, stroke research is highly struggling with a poor clinical translation rate and discussed in depth elsewhere (Pound and Rebecca, 2020). The vast majority of interventions for stroke successfully tested in preclinical animal studies have turned out to either have no efficacy (Horn and Limburg, 2001;Shuaib et al, 2007) or to be harmful to humans (Saxena et al, 1999;Bath et al, 2000;Davis et al, 2000;Enlimomab Acute Stroke Trial Investigators, 2001) and increased the risk of death in clinical trials. From more than 1,000 candidate neuroprotective drugs that where tested in animals, not a single one was found to benefit humans with stroke (O' Collins et al, 2006) and animal studies were just used to establish dosing but did not play a direct role in clinical translation (Pound and Rebecca, 2020).…”

Section: Microbiota and Strokementioning

confidence: 99%

The Microbiota-Gut-Brain Axis in Health and Disease and Its Implications for Translational Research

Schächtle

Rosshart

2021

Front. Cell. Neurosci.

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Over the past decades, microbiome research has evolved rapidly and became a hot topic in basic, preclinical and clinical research, for the pharmaceutical industry and for the general public. With the help of new high-throughput sequencing technologies tremendous progress has been made in the characterization of host-microbiota interactions identifying the microbiome as a major factor shaping mammalian physiology. This development also led to the discovery of the gut-brain axis as the crucial connection between gut microbiota and the nervous system. Consequently, a rapidly growing body of evidence emerged suggesting that the commensal gut microbiota plays a vital role in brain physiology. Moreover, it became evident that the communication along this microbiota-gut-brain axis is bidirectional and primarily mediated by biologically active microbial molecules and metabolites. Further, intestinal dysbiosis leading to changes in the bidirectional relationship between gut microbiota and the nervous system was linked to the pathogenesis of several psychiatric and neurological disorders. Here, we discuss the impact of the gut microbiota on the brain in health and disease, specifically as regards to neuronal homeostasis, development and normal aging as well as their role in neurological diseases of the highest socioeconomic burden such as Alzheimer’s disease and stroke. Subsequently, we utilize Alzheimer’s disease and stroke to examine the translational research value of current mouse models in the spotlight of microbiome research. Finally, we propose future strategies on how we could conduct translational microbiome research in the field of neuroscience that may lead to the identification of novel treatments for human diseases.

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“…12,59 Tirilazad was also associated with a prolonged QTc interval (increase of 7.5 ms; 95% CI, −0.8 to 15.9) and worse outcomes in patients with acute stroke. 40…”

Section: Cardiac Effectsmentioning

confidence: 99%

The Hazard of Negative (Not Neutral) Trials on Treatment of Acute Stroke

2020

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cute stroke has multiple treatment interventions, including strokeunitsforallpatients 1 ;reperfusiontherapies(eg,thrombolysis, thrombectomy), 2-4 aspirin, 5 and hemicraniectomy 6 for acute ischemic stroke; and blood pressure (BP) lowering for hyperacute hemorrhagic stroke. 7 In contrast, other classes of interventions have failed to show efficacy, notably anticoagulation, neuroprotection, and BP lowering for acute ischemic stroke. Although most acute stroke randomized clinical trials (RCTs) have neutral findings (ie, the intervention did not show a significant effect on its primary outcome), a significant proportion have negative outcomes, with the intervention apparently being hazardous. It is inevitable that trials with negative findings will exist; the uncertainty principle that should underpin all RCTs means that although we start with a plausible and defendable idea, unknown factors may lead to a trial having neutral or negative findings. Nevertheless, the number of RCTs with negative outcomes could be limited through improved preclinical study design, delivery, and clinical oversight during trials. By examining acute stroke RCTs with negative outcomes,thesubjectofthisreview,wehopefullycanreducetheirnumber. MethodsIn this review, negative is used in the broad sense that the experimental treatment was associated with 1 or more statistically nega-tive clinical outcomes, whether or not these included the primary outcome. Hence, the intervention may have been associated with more impairment, disability, dependency, death, or serious adverse events (SAEs). In some cases, data monitoring committees (DMCs) or sponsors stopped trials early for hazard on the basis of interim analysis, in which case the relevant outcome may not still be negative once all final outcomes have been collected. Where trials studied 2 or more doses, hazard was more likely to be present at the highest dose, and the following comments tend to relate to this dose.The negative trials referenced here are those known to the authors through their own libraries of references. 8,9 A formal systematic search was not performed, largely because many authors refer to trials with neutral findings as being negative (ie, not positive), which massively reduces the specificity of any electronic search. The distinction between neutral and negative is important both to explain trial results and to assess potential reasons, and the common verbal and written use of negative to mean not positive should be resisted. Interventions cover drugs, biologics, cells, and devices. The review does not cover the large number of acute stroke RCTs with neutral findings and an explanation for these, but often, neutral findings reflect lack of efficacy or small sample size. No tabulated data or statistical analyses were performed.IMPORTANCE While there are a limited number of beneficial treatments for acute stroke (eg, stroke units, reperfusion, aspirin, hemicraniectomy), there are more negative (as opposed to neutral) interventions spanning multiple different mechanisms of act...

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Tirilazad Mesylate in Acute Ischemic Stroke

Cited by 78 publications

References 49 publications

Oxidative Stress in Ischemia/Reperfusion Injuries following Acute Ischemic Stroke

Oxidative Stress in Ischemia/Reperfusion Injuries following Acute Ischemic Stroke

The Microbiota-Gut-Brain Axis in Health and Disease and Its Implications for Translational Research

The Hazard of Negative (Not Neutral) Trials on Treatment of Acute Stroke

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