Rao MuralikrishnaAdibhatla, Senior Scientist, Department of Neurological Surgery,University of Wisconsin-Madison, WI 53792adibhatl@neurosurg.wisc.edu
"J F Hatcher, R J Dempsey"
Submitted January 02, 2002
We read with interest the article on citicoline phase III
clinical studies [1]. The therapeutic action of citicoline is thought to be
due to stimulation of phosphatidylcholine (PtdCho) synthesis in the
injured brain, though evidence is unclear [2]. In this
regard, Figure 1 needs correction. The biosynthesis of PtdCho from 1,2-
diacylglycerol (diglyceride) and CDP-choline forms cytidine 5'-
monophosphate as the other product, not monoacylglycerol (monoglyceride).
Our studies in transient cerebral ischemia suggest that citicoline
might enhance reconstruction (synthesis) of PtdCho and sphingomyelin, but
could inhibit the destructive processes (activation of
phospholipases). [2-5] Citicoline neuroprotection may include: preserving
cardiolipin and sphingomyelin; preserving arachidonic acid content of
PtdCho and phosphatidylethanolamine; partially restoring PtdCho
levels; and stimulating glutathione synthesis and glutathione reductase
activity. The effects of citicoline could be explained by the
attenuation of phospholipase A2 activation and also to a singular
unifying neuroprotective mechanism of this drug [2].
The following points may need to be considered in future clinical
trials:
Patients were
admitted into the clinical studies up to 24 hours after onset of
symptoms, a longer timeframe than is used in most clinical trials. [1] Our studies indicate that citicoline does not provide
neuroprotection if the onset of treatment is delayed by 3 hours. Another factor is the percentage of citicoline that is incorporated into the brain. As noted, all of clinical trials outside the
US used IV administration in contrast to the oral route in US trials.
It is generally believed that bioavailability is the same between oral and
IV methods, but this conclusion was apparently based on absorption and
excretion, not delivery of citicoline to the brain. [6] Animal studies have
shown brain uptake of citicoline (or its metabolites) of only 0.5% with oral
dose, which increased to ~2% when administered. IV Liposome encapsulation
of citicoline increased brain uptake of the drug to 23% of the
administered dose. [7]
In addition, citicoline metabolism
in humans differs from rodents. In rodents, citicoline administration
increases blood plasma levels of cytidine and choline. In humans,
blood plasma levels of uridine but not cytidine are increased due to
cytidine deaminase in the gastrointestinal tract and liver.[8]. It is
believed that uridine must then enter the brain, become phosphorylated to
uridine triphosphate, and then converted to cytidine triphosphate.
It may be necessary to combine citicoline with another
agent targeted to a different pathway due to the multiple mechanisms contributing to ischemic brain injury.
References
1. Clark WM, Wechsler LR, Sabounjian LA, Schwiderski UE. A phase III
randomized efficacy trial of 2000 mg citicoline in acute ischemic stroke
patients. Neurology. 2001;57:1595-1602.
2. Adibhatla RM, Hatcher JF, Dempsey RJ. Citicoline: neuroprotective
mechanisms in cerebral ischemia. J Neurochem. 2002;80:12-23.
3. Adibhatla RM, Hatcher JF, Dempsey RJ. Effects of citicoline on
phospholipid and glutathione levels in transient cerebral ischemia.
Stroke. 2001;32:2376-2381.
4. Rao AM, Hatcher JF, Dempsey RJ. Lipid alterations in transient
forebrain ischemia: possible new mechanisms of CDP-choline
neuroprotection. J Neurochem. 2000;75:2528-2535.
5. Rao AM, Hatcher JF, Dempsey RJ. Does CDP-choline modulate phospholipase
activities after transient forebrain ischemia? Brain Res. 2001;893:268-
272.
6. Secades JJ, Frontera G. CDP-choline: pharmacological and clinical
review. Methods Find Exp Clin Pharmacol. 1995;17:2-54.
7. Fresta M, Wehrli E, Puglisi G. Enhanced therapeutic effect of cytidine-
5'-diphosphate choline when associated with G(M1) containing small
liposomes as demonstrated in a rat ischemia model. Pharm Res. 1995;12:1769
-1774.
8. Wurtman RJ, Regan M, Ulus I, Yu L. Effect of oral CDP-choline on plasma
choline and uridine levels in humans. Biochem Pharmacol. 2000;60:989-992.
We read with interest the article on citicoline phase III clinical studies [1]. The therapeutic action of citicoline is thought to be due to stimulation of phosphatidylcholine (PtdCho) synthesis in the injured brain, though evidence is unclear [2]. In this regard, Figure 1 needs correction. The biosynthesis of PtdCho from 1,2- diacylglycerol (diglyceride) and CDP-choline forms cytidine 5'- monophosphate as the other product, not monoacylglycerol (monoglyceride).
Our studies in transient cerebral ischemia suggest that citicoline might enhance reconstruction (synthesis) of PtdCho and sphingomyelin, but could inhibit the destructive processes (activation of phospholipases). [2-5] Citicoline neuroprotection may include: preserving cardiolipin and sphingomyelin; preserving arachidonic acid content of PtdCho and phosphatidylethanolamine; partially restoring PtdCho levels; and stimulating glutathione synthesis and glutathione reductase activity. The effects of citicoline could be explained by the attenuation of phospholipase A2 activation and also to a singular unifying neuroprotective mechanism of this drug [2].
The following points may need to be considered in future clinical trials:
Patients were admitted into the clinical studies up to 24 hours after onset of symptoms, a longer timeframe than is used in most clinical trials. [1] Our studies indicate that citicoline does not provide neuroprotection if the onset of treatment is delayed by 3 hours. Another factor is the percentage of citicoline that is incorporated into the brain. As noted, all of clinical trials outside the US used IV administration in contrast to the oral route in US trials. It is generally believed that bioavailability is the same between oral and IV methods, but this conclusion was apparently based on absorption and excretion, not delivery of citicoline to the brain. [6] Animal studies have shown brain uptake of citicoline (or its metabolites) of only 0.5% with oral dose, which increased to ~2% when administered. IV Liposome encapsulation of citicoline increased brain uptake of the drug to 23% of the administered dose. [7]
In addition, citicoline metabolism in humans differs from rodents. In rodents, citicoline administration increases blood plasma levels of cytidine and choline. In humans, blood plasma levels of uridine but not cytidine are increased due to cytidine deaminase in the gastrointestinal tract and liver.[8]. It is believed that uridine must then enter the brain, become phosphorylated to uridine triphosphate, and then converted to cytidine triphosphate.
It may be necessary to combine citicoline with another agent targeted to a different pathway due to the multiple mechanisms contributing to ischemic brain injury.
References 1. Clark WM, Wechsler LR, Sabounjian LA, Schwiderski UE. A phase III randomized efficacy trial of 2000 mg citicoline in acute ischemic stroke patients. Neurology. 2001;57:1595-1602. 2. Adibhatla RM, Hatcher JF, Dempsey RJ. Citicoline: neuroprotective mechanisms in cerebral ischemia. J Neurochem. 2002;80:12-23. 3. Adibhatla RM, Hatcher JF, Dempsey RJ. Effects of citicoline on phospholipid and glutathione levels in transient cerebral ischemia. Stroke. 2001;32:2376-2381. 4. Rao AM, Hatcher JF, Dempsey RJ. Lipid alterations in transient forebrain ischemia: possible new mechanisms of CDP-choline neuroprotection. J Neurochem. 2000;75:2528-2535. 5. Rao AM, Hatcher JF, Dempsey RJ. Does CDP-choline modulate phospholipase activities after transient forebrain ischemia? Brain Res. 2001;893:268- 272. 6. Secades JJ, Frontera G. CDP-choline: pharmacological and clinical review. Methods Find Exp Clin Pharmacol. 1995;17:2-54. 7. Fresta M, Wehrli E, Puglisi G. Enhanced therapeutic effect of cytidine- 5'-diphosphate choline when associated with G(M1) containing small liposomes as demonstrated in a rat ischemia model. Pharm Res. 1995;12:1769 -1774. 8. Wurtman RJ, Regan M, Ulus I, Yu L. Effect of oral CDP-choline on plasma choline and uridine levels in humans. Biochem Pharmacol. 2000;60:989-992.