Clinical trials for cytoprotection in stroke

Labiche, Lise A.; Grotta, James C.

doi:10.1007/bf03206567

Cited by 39 publications

(52 citation statements)

References 218 publications

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“…Clinical trials of neuroprotection for ischemic stroke have been surveyed in recent reviews (Cheng et al, 2004;Labiche et al, 2004). The Internet Stroke Center website provides a comprehensive clinical stroke-trial database (Internet Stroke Center, 2007).…”

Section: Proof-of-principlementioning

confidence: 99%

Neuroprotection for ischemic stroke: Past, present and future

2008

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Neuroprotection for ischemic stroke refers to strategies, applied singly or in combination, that antagonize the injurious biochemical and molecular events that eventuate in irreversible ischemic injury. There has been a recent explosion of interest in this field, with over 1000 experimental papers and over 400 clinical articles appearing within the past 6 years. These studies, in turn, are the outgrowth of three decades of investigative work to define the multiple mechanisms and mediators of ischemic brain injury, which constitute potential targets of neuroprotection. Rigorously conducted experimental studies in animal models of brain ischemia provide incontrovertible proof-of-principle that high-grade protection of the ischemic brain is an achievable goal. Nonetheless, many agents have been brought to clinical trial without a sufficiently compelling evidence-based pre-clinical foundation. At this writing, around 160 clinical trials of neuroprotection for ischemic stroke have been initiated. Of the approximately 120 completed trials, two-thirds were smaller early-phase safetyfeasibility studies. The remaining one-third were typically larger (>200 subjects) phase II or III trials, but, disappointingly, only fewer than one-half of these administered neuroprotective therapy within the 4-6 hour therapeutic window within which efficacious neuroprotection is considered to be achievable. This fact alone helps to account for the abundance of "failed" trials.This review presents a close survey of the most extensively evaluated neuroprotective agents and classes and considers both the strengths and weakness of the pre-clinical evidence as well as the results and shortcomings of the clinical trials themselves. Among the agent-classes considered are calcium channel blockers; glutamate antagonists; GABA agonists; antioxidants/radical scavengers; phospholipid precursor; nitric oxide signal-transduction down-regulator; leukocyte inhibitors; hemodilution; and a miscellany of other agents. Among promising ongoing efforts, therapeutic hypothermia, high-dose human albumin therapy, and hyperacute magnesium therapy are considered in detail. The potential of combination therapies is highlighted. Issues of clinical-trial funding, the need for improved translational strategies and clinical-trial design, and "thinking outside the box" are emphasized. Part I: Neuroprotection -from Past to the PresentNeuroprotection for ischemic brain injury has emerged only recently as a topic of serious biomedical inquiry. A MEDLINE survey (PubMed, 2007) reveals virtually no publications on this topic until the early 1990's but a remarkable surge in publications over the past 10 years Correspondence and reprint requests to:

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Section: Proof-of-principlementioning

confidence: 99%

Neuroprotection for ischemic stroke: Past, present and future

2008

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“…Among pharmacological therapies, two possible treatments exist for acute ischaemic stroke: a fast and complete recanalisation of the occluded artery, and protection of the brain from the ischaemic injury. 3 So far, only thrombolysis with recombinant tissue plasminogen activator (rt-PA), administered within the fi rst 4·5 h after the onset of symptoms, is recommended for the treatment of acute ischaemic stroke. 4 Recent research suggests that drugs with the potential to enhance endogenous brain plasticity and repair could reduce acute brain damage and improve functional recovery in animal models of stroke, even when they are administered several hours after the ischaemic event.…”

Section: Introductionmentioning

confidence: 99%

Citicoline in the treatment of acute ischaemic stroke: an international, randomised, multicentre, placebo-controlled study (ICTUS trial)

Dávalos¹,

Álvarez-Sabín²,

Castillo³

et al. 2012

The Lancet

237

157

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“…2) The incidence of adverse effects, such as impaired immune function, decreased cardiac output, pneumonia, and cardiac arrhythmias/bradycardias, is high (14,31). Selective brain cooling (SBC) without reducing body core temperature can theoretically address both problems of whole body cooling.…”

mentioning

confidence: 99%

A theoretical model of selective cooling using intracarotid cold saline infusion in the human brain

Konstas¹,

Neimark²,

Laine³

et al. 2007

Journal of Applied Physiology

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Konstas AA, Neimark MA, Laine AF, Pile-Spellman J. A theoretical model of selective cooling using intracarotid cold saline infusion in the human brain. J Appl Physiol 102: 1329 -1340, 2007. First published December 14, 2006; doi:10.1152/japplphysiol.00805.2006.-A threedimensional mathematical model was developed to examine the transient and steady-state temperature distribution in the human brain during selective brain cooling (SBC) by unilateral intracarotid freezing-cold saline infusion. To determine the combined effect of hemodilution and hypothermia from the cold saline infusion, data from studies investigating the effect of these two parameters on cerebral blood flow (CBF) were pooled, and an analytic expression describing the combined effect of the two factors was derived. The Pennes bioheat equation used the thermal properties of the different cranial layers and the effect of cold saline infusion on CBF to propagate the evolution of brain temperature. A healthy brain and a brain with stroke (ischemic core and penumbra) were modeled. CBF and metabolic rate data were reduced to simulate the core and penumbra. Simulations using different saline flow rates were performed. The results suggested that a flow rate of 30 ml/min is sufficient to induce moderate hypothermia within 10 min in the ipsilateral hemisphere. The brain with stroke cooled to lower temperatures than the healthy brain, mainly because the stroke limited the total intracarotid blood flow. Gray matter cooled twice as fast as white matter. The continuously falling hematocrit was the main time-limiting factor, restricting the SBC to a maximum of 3 h. The study demonstrated that SBC by intracarotid saline infusion is feasible in humans and may be the fastest method of hypothermia induction. therapeutic hypothermia; ischemic stroke; spatial and temporal brain temperature distributions THE CENTRAL NERVOUS SYSTEM is vulnerable to focal and global ischemia resulting from acute ischemic stroke (63) and cardiac arrest (21). Therapeutic hypothermia has been repeatedly shown to be effective in limiting the damage of global and focal ischemia in animal models and clinical studies (6,21).In most clinical studies, hypothermia is induced by surface cooling. Although this is the simplest and most cost-effective option for inducing hypothermia (14), it has two major drawbacks. 1) Several hours are required to reach the target body core temperature. All studies report a 3-to 7-h period for cooling to 32-34°C (26, 52); however, endovascular systemic cooling may be able to accelerate the rate of cooling and improve the efficacy of hypothermia (15).2) The incidence of adverse effects, such as impaired immune function, decreased cardiac output, pneumonia, and cardiac arrhythmias/bradycardias, is high (14, 31). Selective brain cooling (SBC) without reducing body core temperature can theoretically address both problems of whole body cooling.Different methods for SBC have been reported (18). Noninvasive methods most commonly used are cooling caps and helmets. However, th...

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Clinical trials for cytoprotection in stroke

Cited by 39 publications

References 218 publications

Neuroprotection for ischemic stroke: Past, present and future

Neuroprotection for ischemic stroke: Past, present and future

Citicoline in the treatment of acute ischaemic stroke: an international, randomised, multicentre, placebo-controlled study (ICTUS trial)

A theoretical model of selective cooling using intracarotid cold saline infusion in the human brain

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