Treatment of acute cerebral infarction with a choline precursor in a multicenter double-blind placebo-controlled study.

Tazaki, Yuichi; Sakai, Fumihiko; Otomo, E; Kutsuzawa, Takashi; Kameyama, Masakuni; Omae, Teruo; Fujishima, M; Sakuma, Atsushi

doi:10.1161/01.str.19.2.211

Cited by 118 publications

(50 citation statements)

References 14 publications

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“…Clinical stroke trials-Citicoline in doses of 1 g per day for 14 days proved entirely safe (Tazaki et al, 1988). Indeed, the clinical safety of citicoline has been repeatedly confirmed.…”

Section: Phospholipid Precursor: Citicolinementioning

confidence: 96%

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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“…Clinical stroke trials-Citicoline in doses of 1 g per day for 14 days proved entirely safe (Tazaki et al, 1988). Indeed, the clinical safety of citicoline has been repeatedly confirmed.…”

Section: Phospholipid Precursor: Citicolinementioning

confidence: 96%

Neuroprotection for ischemic stroke: Past, present and future

2008

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“…12 In patients with stroke, CIT was associated with neurological improvements. 1,[13][14][15][16] Administration of CIT to stroke patients within 24 hours of symptom onset was…”

mentioning

confidence: 99%

Effects of Citicoline Combined With Thrombolytic Therapy in a Rat Embolic Stroke Model

Andersen

Overgaard

Meden

et al. 1999

Stroke

100

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Background and Purpose-We sought to evaluate the effects of the combination of cytidine-5Ј-diphosphocholine (citicoline) and thrombolysis on infarct size, clinical outcome, and mortality in a rat embolic stroke model. Methods-Eighty-three Sprague-Dawley rats were embolized in the carotid territory with a single fibrin embolus and randomly assigned to the following treatment groups: (1) control (saline), (2) citicoline 250 mg/kg, (3) citicoline 500 mg/kg, (4) recombinant tissue plasminogen activator (rtPA) 5 mg/kg, (5) rtPA 5 mg/kg plus citicoline 250 mg/kg, and (6) rtPA 5 mg/kg plus citicoline 500 mg/kg. rtPA was administered as a continuous intravenous infusion over 45 minutes starting 45 minutes after embolization; citicoline was given intraperitoneally 30 minutes and 24, 48, and 72 hours after embolization. At 96 hours, the brains were fixed and stained by hematoxylin-eosin, and infarct volumes were measured. Neurological scores were determined daily. Results-The median infarct size, measured as percentage of the affected hemisphere, in the control group was 37% (interquartile range, 26% to 69%) compared with 22% (5% to 52%; PϭNS) in group 2, 11% (5% to 34%; PϭNS) in group 3, 24% (12% to 31%; PϭNS) in group 4, 11% (3% to 22%; Pϭ0.02) in the combined group 5, and 19% (9% to 51%; PϭNS) in group 6. The infarct size was significantly reduced in the combined citicolineϩrtPA-treated groups to a median of 13% (5% to 30%; PϽ0.01). Citicoline 500 mg/kg and citicoline combined with rtPA also promoted functional recovery. Conclusions-These results demonstrate that the combination of low-dose citicoline and rtPA significantly reduced infarct size in this focal ischemia model.

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“…There have also been preclinical studies reporting enhanced efficacy when citicoline was administered along with or following intravenous thrombolysis [127][128][129], and along with other potential neuroprotective therapies, such as mild hypothermia [130]. Multiple, randomized clinical stroke trials have investigated citicoline and reported that administration of citicoline was effective early in the post-ischemia recovery process, as demonstrated by improved level of consciousness [131], and improvements in the modified Rankin score [132]. Oral treatment with citicoline within the first 24 hours after onset of moderate to severe stroke was reported to increase the probability of complete recovery at 3 months in a meta-analysis of 4 randomized clinical trials, with the highest favorable response observed in the 2000-mg dose group [133].…”

Section: Citicolinementioning

confidence: 99%

Investigational Therapies for Ischemic Stroke: Neuroprotection and Neurorecovery

2011

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Stroke is one of the leading causes of death and disability worldwide. Current treatment strategies for ischemic stroke primarily focus on reducing the size of ischemic damage and rescuing dying cells early after occurrence. To date, intravenous recombinant tissue plasminogen activator is the only United States Food and Drug Administration approved therapy for acute ischemic stroke, but its use is limited by a narrow therapeutic window. The pathophysiology of stroke is complex and it involves excitotoxicity mechanisms, inflammatory pathways, oxidative damage, ionic imbalances, apoptosis, angiogenesis, neuroprotection, and neurorestoration. Regeneration of the brain after damage is still active days and even weeks after a stroke occurs, which might provide a second window for treatment. A huge number of neuroprotective agents have been designed to interrupt the ischemic cascade, but therapeutic trials of these agents have yet to show consistent benefit, despite successful preceding animal studies. Several agents of great promise are currently in the middle to late stages of the clinical trial setting and may emerge in routine practice in the near future. In this review, we highlight select pharmacologic and cell-based therapies that are currently in the clinical trial stage for stroke.

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Treatment of acute cerebral infarction with a choline precursor in a multicenter double-blind placebo-controlled study.

Cited by 118 publications

References 14 publications

Neuroprotection for ischemic stroke: Past, present and future

Neuroprotection for ischemic stroke: Past, present and future

Effects of Citicoline Combined With Thrombolytic Therapy in a Rat Embolic Stroke Model

Investigational Therapies for Ischemic Stroke: Neuroprotection and Neurorecovery

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