A phase III randomized efficacy trial of 2000 mg citicoline in acute ischemic stroke patients

Clark, Wayne M.; Wechsler, Lawrence R.; Sabounjian, LuAnn; Schwiderski, Ute

doi:10.1212/wnl.57.9.1595

Cited by 171 publications

(140 citation statements)

References 22 publications

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“…In all these studies, citicoline had a similar safety profi le as compared with placebo. 8 Despite some post-hoc positive results in subgroups of stroke patients, [9][10][11] primary endpoints failed to show effi cacy. In a pooled analysis with individual patient data of randomised clinical trials, oral citicoline at doses between 500 mg and 2000 mg per day were associated with an odds ratio of 1·33 (95% CI 1·10-1·62) in complete functional and neurological recovery when compared with placebo in patients with moderate-to-severe acute ischaemic stroke.…”

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

241

157

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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

241

157

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“…Decades of intensive searching for neuroprotective drugs against cerebral ischemia/ischemic stroke have met many preclinical but not clinical successes (1)(2)(3)(4)(5)(6)(7)(8). The only option currently available for the treatment of ischemic stroke is the thrombolytic therapy (such as, the recombinant tissue plasminogen activator), which must be administered within 3 h after the episode to achieve early arterial recanalization.…”

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confidence: 99%

Postischemic PKC activation rescues retrograde and anterograde long-term memory

Sun

Hongpaisan

Alkon

2009

Proc. Natl. Acad. Sci. U.S.A.

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Therapeutics for cerebral ischemia/hypoxia, which often results in ischemic stroke in humans, are a global unmet medical need. Here, we report that bryostatin-1, a highly potent protein kinase C (PKC) activator, interrupts pathophysiological molecular cascades and apoptosis triggered by cerebral ischemia/hypoxia, enhances neurotrophic activity, and induces synaptogenesis in rats. This postischemic therapeutic approach is further shown to preserve learning and memory capacity even 4 months later as well as long-term memory induced before the ischemic event. Our results of electromicroscopic and immunohistochemical analyses of neuronal and synaptic ultra-structure are consistent with a PKC-mediated synaptic remodeling and repair process that confers long-lasting preservation of spatial learning and memory before and after the cerebral ischemic/hypoxic event, suggesting a previously undescribed therapeutic modality for cerebral ischemia/hypoxia and ischemic stroke.bryostatin ͉ protein kinase C ͉ stroke therapy ͉ synaptogenesis C erebral ischemia/hypoxia, which often results in stroke, is the third leading cause of death and the most common cause of long-term disability in the developed countries. Decades of intensive searching for neuroprotective drugs against cerebral ischemia/ischemic stroke have met many preclinical but not clinical successes (1-8). The only option currently available for the treatment of ischemic stroke is the thrombolytic therapy (such as, the recombinant tissue plasminogen activator), which must be administered within 3 h after the episode to achieve early arterial recanalization. Several factors most likely contribute the translational failures. Targeting mainly the pathological cascades induced by ischemia/hypoxia (arresting the pathological pathway), such as extracellular build up of excitatory aminio acids and intracellular Ca 2ϩ elevation, is most effective when the blockers are given at or immediately before an ischemic event. Furthermore, the targeted neurotransmitters, Ca 2ϩ , and many enzymes involved in the ischemic/hypoxic responses are also critical for neuronal functions so that their effective blockade cannot be maintained without producing serious adverse effects or toxicity. In addition, the short-term effectiveness of agents arresting the pathological pathway as determined in most preclinical studies, does not guarantee a cure, because such drug candidates may delay but not prevent the pathological impact (9).We have recently found that, instead of only arresting the pathological cascades in cerebral ischemia, postischemic (24 h after) bryostatin-1, a relatively isoform-selective protein kinase C (PKC) activator with antiapoptotic and synaptogenesisfacilitating properties (10-13), rescues rats from ischemic/ hypoxic impairment of spatial learning and memory (14), evaluated about 2 weeks after the end of a 5-week treatment. ResultsHere, we investigated therapeutic effects of postischemic bryostatin-1 in two paradigms: one involving long-term anterograde, and the other retrogra...

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“…68 Four clinical trials of citicoline have shown no differences in their primary outcome measures. [19][20][21]153 Although a pooled analysis of 1372 participants with baseline NIHSS scores ≥ 8 showed a statistically significant effect of citicoline on 3-month global outcome incorporating NIHSS, mRS, and Barthel Index scores at 3 months (25.2% vs 20.2%; p = 0.0034), these trials were limited by multiple design flaws. 23 The most recent International Citicoline Trial on Acute Stroke (ICTuS), which evaluated 2298 patients in a multicenter RCT, showed that global recovery was similar in both groups (OR 1.03; p = 0.364).…”

Section: Antioxidant Agentsmentioning

confidence: 99%

Neuroprotective strategies and the underlying molecular basis of cerebrovascular stroke

Karsy¹,

Brock²,

Guan³

et al. 2017

FOC

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Stroke is a leading cause of disability in the US. Although there has been significant progress in the area of medical and surgical thrombolytic technologies, neuroprotective agents to prevent secondary cerebral injury and to minimize disability remain limited. Only limited success has been reported in preclinical and clinical trials evaluating a variety of compounds. In this review, the authors discuss the most up-to-date information regarding the underlying molecular biology of stroke as well as strategies that aim to mitigate this complex signaling cascade. Results of historical research trials involving N-methyl-d-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor antagonists, clomethiazole, antioxidants, citicoline, nitric oxide, and immune regulators have laid the groundwork for current progress. In addition, more recent studies involving therapeutic hypothermia, magnesium, albumin, glyburide, uric acid, and a variety of other treatments have provided more options. The use of neuroprotective agents in combination or with existing thrombolytic treatments may be one of many exciting areas of further development. Although past trials of neuroprotective agents in ischemic stroke have been limited, significant insights into mechanisms of stroke, animal models, and trial design have incrementally improved approaches for future therapies.

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A phase III randomized efficacy trial of 2000 mg citicoline in acute ischemic stroke patients

Abstract: Citicoline was safe but ineffective in improving the outcome of patients with acute ischemic stroke as measured by the planned analyses. Post hoc analyses suggest that a modest treatment effect may have been seen if more traditional analyses had been used.

Cited by 171 publications

References 22 publications

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

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

Postischemic PKC activation rescues retrograde and anterograde long-term memory

Neuroprotective strategies and the underlying molecular basis of cerebrovascular stroke

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