Cytidine does not affect acute toxicity of intravenously administered choline.

Cytidine-5'-diphosphocholine (CDP-choline) is a key precursor for the intracellular synthesis of phosphatidylcholine and other phospholipids. Following either intravenous or oral application citicoline (CDP-choline of exogenous origin) undergoes quick decomposition to cytidine and choline, and for this reason it is frequently considered a prodrug. However, upon acute intravenous application in mice citicoline is, on a molar basis, 20 times less toxic than choline. To find out whether cytidine may attenuate toxicity of choline, in the present experiments we compared maximum tolerated doses of single intravenous injections of choline and equimolar mixture of choline and cytidine. We assumed that, if after oral intake a substantial part of citicoline is catabolised already in the intestine and its catabolites enter blood separately, intravenously applied equimolar mixture of cytidine and choline will be markedly less toxic than an equivalent molar dose of choline. However, the maximum tolerated single doses determined in our experiment for choline and equimolar mixture of choline and cytidine were similar. These data suggest that citicoline taken orally is not significantly decomposed in the intestinal lumen, but absorbed to blood as the intact molecule.

Citicoline: pharmacological and clinical review, 2010 update.

This review is based on the previous one published in 2006 -Secades JJ, Lorenzo JL. Citicoline: pharmacological and clinical review, 2006 update. Methods Find Exp Clin Pharmacol 2006; 28 (Suppl B): S1-56-, incorporating the new references until now, having all the information available to facilitate the access to the informacion in one document. This review is focused on the main indications of the drug, as acute stroke and its sequelae, including the cognitive impairment, and traumatic brain injury and its sequelae. There are retrieved the most important experimental and clinical data in both indications.

Single- and repeated-dose oral toxicity studies of citicoline free-base (choline cytidine 5'-pyrophosphate) in Sprague-Dawley rats.

The dietary supplement Citicoline free-base (choline cytidine 5'-pyrophosphate) was toxicologically evaluated in Sprague-Dawley rats using oral gavage. In an acute 14-day study, 2000 mg/kg was well tolerated. In a 90-day study, 100, 350, and 1000 mg/kg/day doses resulted in no mortality. In males, slight significant increases in serum creatinine (350 and 1000 mg/kg/day), and decreases in urine volume (all treated groups) were observed. In females, slight significant increases in total white blood cell and absolute lymphocyte counts (1000 mg/kg/day), and blood urea nitrogen (BUN) (100 and 350, but not 1000 mg/kg/day) were noted. A dose-related increase in renal tubular mineralization, without degenerative or inflammatory reaction, was found in females (all treated groups) and two males (1000 mg/kg/day). Renal mineralization in rats (especially females) is influenced by calcium:phosphorus ratios in the diet. A high level of citicoline consumption resulted in increased phosphorus intake in the rats, and likely explains this result.

Citicoline: pharmacological and clinical review, 2006 update.

Cytidine 5'-diphosphocholine, CDP-choline, or citicoline is an essential intermediate in the biosynthetic pathway of structural phospholipids in cell membranes, particularly phosphatidylcholine. Following administration by both the oral and parenteral routes, citicoline releases its two main components, cytidine and choline. Absorption by the oral route is virtually complete, and bioavailability by the oral route is therefore approximately the same as by the intravenous route. Once absorbed, citicoline is widely distributed throughout the body, crosses the blood-brain barrier and reaches the central nervous system (CNS), where it is incorporated into the membrane and microsomal phospholipid fraction. Citicoline activates biosynthesis of structural phospholipids of neuronal membranes, increases brain metabolism, and acts upon the levels of different neurotransmitters. Thus, citicoline has been experimentally shown to increase norepinephrine and dopamine levels in the CNS. Owing to these pharmacological mechanisms, citicoline has a neuroprotective effect in hypoxic and ischemic conditions, decreasing the volume of ischemic lesion, and also improves learning and memory performance in animal models of brain aging. In addition, citicoline has been shown to restore the activity of mitochondrial ATPase and membrane Na+/K+ATPase, to inhibit activation of certain phospholipases, and to accelerate reabsorption of cerebral edema in various experimental models. Citicoline has also been shown to be able to inhibit mechanisms of apoptosis associated to cerebral ischemia and in certain neurodegeneration models, and to potentiate neuroplasticity mechanisms. Citicoline is a safe drug, as shown by the toxicological tests conducted, that has no significant systemic cholinergic effects and is a well tolerated product. These pharmacological characteristics and the action mechanisms of citicoline suggest that this product may be indicated for treatment of cerebral vascular disease, head trauma (HT) of varying severity, and cognitive disorders of different causes. In studies conducted in the treatment of patients with HT, citicoline was able to accelerate recovery from post-traumatic coma and neurological deficits, achieving an improved final functional outcome, and to shorten hospital stay in these patients. Citicoline also improved the mnesic and cognitive disorders seen after HT of minor severity that constitute the so-called post-concussional syndrome. In the treatment of patients with acute ischemic cerebral vascular disease, citicoline accelerates recovery of consciousness and motor deficit, achieves a better final outcome, and facilitates rehabilitation of these patients. The other major indication of citicoline is for treatment of senile cognitive impairment, either secondary to degenerative diseases (e.g. Alzheimer disease) or to chronic cerebral vascular disease. In patients with chronic cerebral ischemia, citicoline improves scores in cognitive rating scales, while in patients with senile dementia of the Alzheimer type it stops the course of disease, and neuroendocrine, neuroimmunomodulatory, and neurophysiological benefits have been reported. Citicoline has also been shown to be effective in Parkinson disease, drug addictions, and alcoholism, as well as in amblyopia and glaucoma. No serious side effects have occurred in any series of patients treated with citicoline, which attests to the safety of treatment with citicoline.

Dissimilar effects in acute toxicity studies of CDP-choline and choline.

The LD50 and LD0 of choline HCl and cytidine diphosphate choline (CDP-choline, citicoline, Somazina) by oral and intravenous route at equivalent doses of choline for both compounds were determined. The qualitative and quantitative analysis of the results obtained lead to the conclusion that choline shows a remarkable cholinergic action, while CDP-choline both orally and intravenously does not cause any cholinergic intoxication in the treated groups, like those recorded for choline administration. It should be emphasized that when the quantity of choline contained in CDP-choline administered was identical to that of choline with which the animal group was treated showing signs of cholinergic crisis, the animals corresponding to CDP-choline did not show any of these symptoms. Objective evaluation showed that CDP-choline by oral and intravenous route does not behave like a choline groups donator, at least not with an intensity which would make us believe that its only action was due to the increased levels of choline; this proves that CDP-choline administration yields clearly differentiated metabolic consequences from those yielded by choline administration.

CDP-choline: acute toxicity study.

The acute toxicity of a single dose of cytidine diphosphate choline (CDP-choline, citicoline, Somazina) by different administration routes in mice and rats has been studied. LD50 values were determined according to the cumulative method by Reed-Muench for mortality rate, and Pizzi's method for calculation of standard error.

Study of subacute toxicity of CDP-choline after 30 days of oral administration to rats.

Two groups of rats were administered by oral route doses of 100 and 150 mg/kg, respectively, of cytidine diphosphate choline (CDP-choline citicoline, Somazina), daily during 30 days. At the end of the test, animals were killed and necropsied, evaluating the urinary, haematological, serum biochemistry and histopathological parameters. The study did not reveal any signs of toxicity.

CDP-choline: 6-month study on toxicity in dogs.

A single oral dose of 1.5 g/kg cytidine diphosphate choline (CDP-choline, citicoline, Somazina) was administered to 6 Beagle dogs daily for 6 months. After treatment period, treated animals as well as control animals were sacrificed and assessment of urinalysis, blood analysis and histopathological studies were made. Results were found within normal ranges--involving slight changes due to individual variability. It can therefore be concluded that CDP-choline does not cause any toxic effects under the chosen experimental conditions.

Action of CDP-choline by intraduodenal route on rat cardiorespiratory system.

The influence of an acute treatment with cytidine diphosphate choline (CDP-choline, citicoline, Somazina) by intraduodenal route on cardiovascular and respiratory parameters in anesthetized rats is studied. No differences as compared with controls were observed in heart and respiratory rates. The values in arterial pressure and respiratory flow for CDP-choline groups were observed to be near the basal values. The inspiratory flow shows a statistically significant difference (approaching basal values) as compared with the decrease in controls.