By Candice Cryne, MSc.
July 15, 2011

As medical science and technology advances, so does the average life expectancy. However, this increase in life expectancy comes with a greater risk of developing a plethora of age-related diseases including, but not limited to cardiovascular disease, stroke, diabetes, osteoporosis, cancer, arthritis, and dementia.

The number of individuals suffering from dementia is projected to double in Canada over the next 25 years from half a million to 1.1 million (Alzheimer’s Society, 2010).

The onset of dementia (Alzheimer ’s disease is the most common type of dementia) is associated with a variety of ailments including Parkinson’s disease, Multiple Sclerosis, Lewy Body Disease, Huntington’s Disease, viral or bacterial infections and tumors etc.

Furthermore, experiencing a stroke has been shown to considerably increase the likelihood of dementia in the elderly (Ivan et al., 2004). Post-stroke vascular dementia (VaD) affects 30% of survivors, and the incidence of new-onset dementia increases from 7% 1 year after stroke to 48% after 25 years (Leys et al., 2005).

There has been a substantial amount of prescription medication and natural products purported to treat or reduce the risk of dementia. Currently citicoline is sold around the world as a natural health product or dietary supplement. Within Health Canada’s Natural Health Product Ingredients Database, this ingredient is unrestricted and is classified as a medicinal ingredient.

Physiologically, citicoline is a naturally occurring endogenous nucleoside that functions as an intermediate in 3 major metabolic pathways (Sabin and Roman, 2010). “Citicolin formation is the rate limiting step in the synthesis of phosphatidylcholine (lecithin) in neuronal membranes and microsomal phospholipids; citicoline provides choline for acetylcholine synthesis and could limit choline availability for membrane synthesis; and oxidation to betaine, a methyl donor (Sabin and Roman, 2010)”. Furthermore, citicoline has been found to be readily absorbed in the gut, cross the blood-brain barrier (Conant et al., 2004) and demonstrate a bioavailabllity of 100% after oral administration (Davalos et al., 2002).

In the 1990’s, the clinical development of citicoline for the treatment of acute ischemic stroke was initiated in the United States (Davalos et al., 2002). Phase II-III clinical trials were conducted to evaluate the effects of 500, 1000 and 2000 mg/d of citicoline compared to placebo. The 500 and 2000 mg dose resulted in significant improvement of neurological (National Institute of Health Stroke Scale [NIHSS]), functional (Barthel Index [BI]), and global (modified Rankin Scale [mRS]) outcomes compared to placebo over 12 weeks (Clarke et al., 1997, Clarke et al., 1999). However, the last trial conducted to confirm the effects of 2000 mg/d of citicoline on neurological and functional outcomes of patients with moderate to severe ischemic stroke did not demonstrate any significant improvement when evaluated using the NIHSS scale, which was the primary endpoint for assessing neurological function (Clarke et al., 2001). Since there was discrepancy between the studies, Davalos et al., 2002 performed a meta-analysis of individual patient data to test whether treatment with oral citicoline for 6 weeks improves overall recovery at 3 months for patients with acute ischemic stroke. The results found that recovery at 3 months was 25.2% in citicoline-treated patients and 20.2% in placebo treated patients (P = 0.0034), with the highest favourable response in the 2000 mg citicoline group (P = 0.045). Furthermore, citicoline significantly increased the probability to recover activities of daily living by 29% and probability to recover function capacity (mRS) by 42%. In a recent review paper from Davalos and Secades, 2011, they described two major clinical trials that are underway to further evaluate the efficacy of citicoline. The Citicoline Brain Injury Treatment trial (COBRIT), conducted in the United States, is a randomized, double-blind, placebo-controlled, multicenter trial designed to analyze the effects of 90 days of citicoline (1g twice daily) or placebo supplementation on functional outcome in patients with complicated mild, moderate, or severe traumatic brain injury. The sample size is approximately 1500 patients, and the results are expected late 2011. In Europe, the International Citicoline Trial on Acute Stroke (ICTUS) trial is underway and actively recruiting patients.

ICTUS is a multicenter, randomized (under minimization), double-blind, placebo-controlled trial whichwill follow a sequential analysis (triangular model), with 2600 patients. This design has 80% power to establish a treatment effect of 1.26 (common odds ratio). The primary end point will consist of a global score test combining 3 measures of success evaluated 12 weeks after treatment on the basis of intention-to-treat criteria: neurological (NIHSS score ≥1), disability (modified Rankin scale score ≤1), and activities of daily life (Barthel Index score ≥95), all averaged using a global test (Davalos and Secades, 2011).

In addition to neurologicl benefits in stroke victims, citicoline has shown potential in the field of ophthalmology. Citicoline has demonstrated a significant action in improving retinal and cortical responses in patients with optic nerve diseases (glaucoma, ischemic optic neuropathy). An efficacy study is currently underway to demonstrate whether daily oral administration of citicoline in patients treated for uveal melanomas with proton beam therapy, prevents or delays the occurrence of radiation optic neuropathy. Changes in visual acuity, pattern ERG and visual evoked potentials are to be measured (Clinicaltrails.gov #NCT01338389).

In the next coming years, it will be interesting to see if the efficacy of this naturally occurring endogenous nucleoside can be proven to help prevent stroke related dementia, as the safety and tolerance is excellent with very few side effects (Davalos and Secades, 2011).

References:

Alzheimer’s Society. Alzheimer’s Disease Statistics. Key Facts about Alzheimer’s Disease and Related Dementia. http://www.alzheimer.ca/english/disease/stats-intro.htm Accessed July 15, 2011

Clark WM, Warach SJ, Pettigrew LC, Gammans RE, Sabounjian LA. A randomized dose-response trial of citicoline in acute ischemic stroke patients. Citicoline Stroke Study Group. Neurology. 1997;49:671– 678.

Clark WM, Williams BJ, Selzer KA, Zweifler RM, Sabounjian LA, Gammans RE. A randomized efficacy trial of citicoline in patients with acute ischemic stroke. Stroke. 1999;30:2592–2597.

Clark WM, Wechsler LR, Sabounjian LA, Schwiderski UE, Citicoline Stroke Study Group. A phase III randomized efficacy trial of 2000 mg citicoline in acute ischemic stroke patients. Neurology 2001;57: 1595–1602.

Conant R, Schauss AG. Therapeutic applications of citicoline for stroke and cognitive dysfunction in the elderly: a review of the literature. Altern Med Rev. 2004;9:17–31.

Davalos A, Castillo J, Alvarez-Sabín J, Secades JJ, Mercadal J, Lo´pez S, Cobo E, Warach S, Sherman D, Clark WM, Lozano R. Oral citicoline in acute ischemic stroke: an individual patient data pooling analysis of clinical trials. Stroke. 2002;33:2850 –2857.

Dávalos A, Secades J. Citicoline preclinical and clinical update 2009-2010.

Stroke. 2011 Jan;42(1 Suppl):S36-9. Epub 2010 Dec 16. Review.

Ivan CS, Seshadri S, Beiser A, Au R, Kase CS, Kelly-Hayes M, Wolf PA. Dementia after stroke: the Framingham Study. Stroke. 2004;35: 1264–1268.

Leys D, He´non H, Mackowiak-Cordoliani MA, Pasquier F. Poststroke dementia. Lancet Neurol. 2005;4:752–759.

Warach S, Pettigrew LC, Dashe JF, Pullicino P, Lefkowitz DM, Sabounjian L, Harnett K, Schwiderski U, Gammans R. Effect of citicoline on ischemic lesions as measured by diffusion-weighted magnetic resonance imaging. Citicoline 010 Investigators. Ann Neurol. 2000;48:713–722.