Citicoline

Authors:

Sherief Ghozy

Findings:

This literature review discusses current management strategies for acute ischemic stroke (AIS), focusing on various neuroprotective agents, their mechanisms of action, and the evidence for their effectiveness. The review highlights the time-critical nature of AIS management, the limitations of current therapies, and the ongoing search for effective neuroprotection, calling for further validation of promising modalities through rigorous trials.

Participants:

The review discusses studies involving human participants (e.g., 'patients with acute ischemic stroke (AIS)', 'patients with acute stroke', 'elderly patients with acute ischemic stroke', 'patients with large hemispheric infarction', 'critically ill patients') and preclinical animal models (e.g., 'rat stroke model', 'rodents', 'mice', 'macaques'). Information is drawn from reviewed literature, including clinical trials detailed in Table 1.

Dosage:

The review cites dosages from various studies it discusses, including: rtPA (intravenously within 3-6 hours); Tenecteplase (single bolus); NXY-059 (intravenously within 6 hours or 72-hour IV infusion); Magnesium sulfate (prehospital application within 2 hours of stroke onset); NA-1 (pretreatment before endovascular aneurysm surgery); Lovastatin (8 mg/kg 3 days post-AIS); Atorvastatin Calcium (20 mg daily for 12 months, or 40–80 mg daily for 6 months, as per NCT03753555); Glibenclamide (loading dose of 1.25 mg within 10h of stroke onset, then 0.625 mg every 8h for 5 days orally/gastric tube, or intravenous, as per NCT03284463 and NCT02864953); Insulin (standard therapy for blood glucose 80-179 mg/dL or intensive therapy for 80-130 mg/dL, intranasal in animal studies); Neu2000KWL (nine consecutive infusions at 12-hour intervals, before EVT or within 6h of stroke onset, with low, middle, or high doses); Nimodipine (IV or other routes); Edaravone (IV); DLBS 1033 (490 mg tablet 3 times daily, as per NCT04425590); Rosuvastatin 10 mg plus Ezetimibe 10 mg combination once daily for 90 days (as per NCT03993236); Argatroban (plus standard medical treatment, as per NCT04275180); Exenatide injections (as per NCT03287076).

Study Quality Assessment:

This is a literature review published in 'Front Neurol . 2022 May 31;13:870141'. Its methodology involved a comprehensive search of EMBASE, Medline, and Cochrane library for English-language studies, using MeSH terms, and an additional manual search of references. The article was edited and peer-reviewed by named individuals. It is an open-access article under a Creative Commons Attribution License (CC BY). The authors declared no conflict of interest. The review includes a table summarizing numerous ongoing clinical trials, many of which are specified as Randomized Controlled Trials (RCTs).

All Effects:

Authors:

Surojit Paul

Findings:

This narrative review provides an overview of current neuroprotective therapies for acute ischemic stroke (AIS), examining recent clinical evidence for pharmacologic agents (e.g., nerinetide, edaravone, uric acid, S44819, Xuesaitong soft capsules, exenatide, edaravone dexborneol, GDLM, fluoxetine) and nonpharmacological interventions (e.g., remote ischemic conditioning, normobaric hyperoxia, MSC therapy, C-tDCS). While many preclinical neuroprotective methods show benefits in animal models, translation to human clinical trials has often failed, though some agents like edaravone dexborneol and Xuesaitong soft capsules have reported promising clinical results. The review discusses reasons for trial failures and suggests future directions, including adjunctive use with recanalization therapies, improved preclinical models reflecting patient comorbidities, multi-target drugs, and prehospital initiation of treatments.

Participants:

The review discusses studies involving human participants (Acute Ischemic Stroke (AIS) patients with varying inclusion criteria detailed in specific trials, e.g., age, NIHSS score, time from onset, type of stroke) and animal models (noting that preclinical studies often use male and healthy animals, which may not adequately replicate patient heterogeneity).

Dosage:

The review reports dosages from various clinical trials it discusses, including: Nerinetide (NA-1) as a single dose of 2.6 mg/kg after EVT; S44819 at 150 mg or 300 mg twice a day for 90 days; Xuesaitong soft capsules at 120 mg orally twice daily for 3 months; Exenatide at 5 μg subcutaneous injection twice daily for 5 days; Edaravone dexborneol (edaravone 30 mg; (+)-borneol 7.5 mg) or edaravone (30 mg) injection once every 12 hours for 14 days; Ginkgo diterpene lactone meglumine (GDLM) at 25 mg once daily for 14 days; Fluoxetine at 20 mg orally once daily for 6 months; Transdermal glyceryl trinitrate at 5 mg/day for 24 hours; Cathodal transcranial direct current stimulation (C-tDCS) at 1.5 mA for 20-min epochs, every hour over 6 h and 20 min.

Study Quality Assessment:

The document is a 'narrative review'. It discusses 'strengths and weaknesses of certain clinical trials'. It highlights limitations of preclinical studies (e.g., use of healthy male animals, not replicating patient heterogeneity with comorbidities) and clinical trials (e.g., delayed drug administration, enrollment of patients without concomitant reperfusion therapies, use of lower doses for safety, reliance on mRS as a primary outcome measure which may lack sensitivity for subtle changes). Funding for the review is disclosed: 'National Natural Science Foundation of China (82422024), the Beijing Natural Science Foundation (JQ22020), Beijing Nova Program (Z201100006820143)'. The article is published in an 'open access journal' under the 'Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License'. A conflict of interest is declared: 'Wenbo Zhao is an Associate Editor of Brain Circulation. The article was subject to the journal’s standard procedures, with peer review handled independently of the Editor and their research groups.'

All Effects:

Authors:

Kamil Synoradzki, Paweł Grieb

Findings:

This review posits citicoline as a potentially superior form of choline, emphasizing its lower acute toxicity compared to choline and hypothesizing less conversion to trimethylamine (TMA) and its N-oxide (TMAO), which could make it a safer supplement. Citicoline supplementation is suggested to be more efficacious for procognitive effects than choline or phosphatidylcholine, with studies indicating improvements in memory, attention, psychomotor speed, and behavior in various populations, including those with cognitive impairments or dementia (where it may improve efficacy of cholinesterase inhibitors).

Participants:

The review discusses studies involving various populations: 'middle-aged to elderly adults' as a target for food supplements; 'non-demented individuals (1391 subjects, mean age 60.9 years)'; '2195 subjects aged 70–74 years'; 'adolescent males'; 'adult patients suffering from cognitive impairments, especially of vascular origin'; 'elderly' with chronic cerebral disorders; 'patients suffering from dementia'. Animal models mentioned include 'rats' and 'mice' for toxicity and metabolism studies.

Dosage:

For food supplements aimed at middle-aged to elderly adults, a maximum level of 500 mg/day is mentioned. For dietary foods for special medical purposes, a maximum dose of 250 mg per serving and a maximum daily consumption level of 1000 mg is noted. A rat study involved a single oral administration of a high dose of citicoline (1 g/kg b.w.).

Study Quality Assessment:

The text is a review article that cites various study types including 'Epidemiological studies', 'placebo-controlled study', 'controlled studies', 'placebo-controlled trials', 'cross-sectional study', and a 'meta-analysis'. It references specific sample sizes from cited studies (e.g., '1391 subjects', '2195 subjects'). For the review itself, it states: 'This research received no external funding.' and 'The authors declare no conflict of interest.' The review also discusses EFSA scientific opinions and regulatory decisions.

All Effects:

Authors:

Stephanie C Dulawa

Study Quality Assessment:

Published in Molecular Psychiatry (IF 9.6). Mentions 'basic and clinical studies'.

Authors:

Pawel Grieb

Findings:

Citicoline, chemically identical to the natural precursor of phosphatidylcholine, has shown neuroprotective activity in preclinical models of brain ischaemia and trauma. However, two recent, large clinical trials (ICTUS and COBRIT) revealed no benefits in ischaemic stroke and traumatic brain injury. The substance may be beneficial in some slowly advancing neurodegenerative disorders like glaucoma and mild vascular cognitive impairment, but its mechanism of action, pharmacokinetics, and biotransformation are not fully understood, leading to doubts and unresolved issues regarding its clinical pharmacology.

Participants:

The review discusses studies involving: preclinical animal models (e.g., rats, mice, dogs for ischaemia, trauma, toxicity studies); human subjects including healthy volunteers (pharmacokinetics), patients with acute ischaemic stroke (e.g., ICTUS trial, N=2,298; study by Cho and Kim, N=4,191 Korean stroke patients), traumatic brain injury (e.g., COBRIT trial, N=1,213), glaucoma, and mild vascular cognitive impairment (e.g., IDEALE study).

Dosage:

The usual daily therapeutic dosage of citicoline in humans is 500–2,000 mg (equivalent to 7–28 mg/kg for a 70kg person). Human pharmacokinetic studies involved oral doses up to 4g, and one study used 1,000 mg tablets. For sub-acute ischaemic cerebrovascular disease, an intravenous dose of 2,000 mg for 5 or 10 days was mentioned. Animal studies reported LD50 values (e.g., oral approx. 8 g/kg in mice/rats; i.v. 4,600 mg/kg in mice, 4,150 mg/kg in rats) and neuroprotective effects at 0.3–1 g/kg. A rat oral toxicity study used 100–1,000 mg/kg daily doses for 90 days. Some animal experiments used doses like 1,000 mg/kg intraperitoneally.

Study Quality Assessment:

The review analyzes preclinical studies, large randomized placebo-controlled multicenter clinical trials (e.g., ICTUS trial with 2,298 patients for ischaemic stroke; COBRIT trial with 1,213 patients for traumatic brain injury), meta-analyses of placebo-controlled trials (e.g., 1,652 actively treated and 686 placebo-treated subjects for adverse effects), and observational studies (e.g., open IDEALE study). Methodologies mentioned from cited studies include LC–ESI–MS/MS, phosphorous magnetic resonance spectroscopy, and proton magnetic resonance spectroscopy (MRS). The review highlights unresolved issues such as the lack of an adequate description of citicoline's mechanism of action, discrepancies between animal and human clinical results, and concerns about excessively large doses used in many animal experiments. The literature search for this review was performed in PubMed, Scopus, and Web of Science databases.

All Effects: