1. Stroke and Neuroprotection

2. Stroke: Definition
A syndrome characterized by acute onset of a neurologic
deficit that persists for at least 24 hours, reflects focal
involvement of the central nervous system, and is the result
of a disturbance of the cerebral circulation.

3. Stroke : A silent epidemic
• Stroke the second leading cause of death and major cause of
disability worldwide1,2
• Two-thirds of stroke deaths occur in developing countries1,2
• In India, the incidence and 30 day case fatality rates are
higher than that in developed countries3,4
• Significant increase in noncommunicable diseases such as
stroke and CAD in both urban and rural India 2
1. .Donnan GA, Fisher M, et al, Lancet 2008;371:1612-23
2. .Pandian JD, Srikanth V, et al, Stroke 2007;38:3063-9
3. .Das K, Banerjee TK, et al, Stroke 2007;38:906-10
4. .Dalal P, Bhattacharjee M, et al, Indian Acad Nerolol 2007;10:130-6

4. Stroke in India
• During the last decade, the age-adjusted prevalence rate of
stroke was between 250-350/100,000.
• Recent studies showed that the age-adjusted annual
incidence rate was 105/100,000 in the urban community of
Kolkata and 262/100,000 in a rural community of Bengal.
• The ratio of cerebral infarct to hemorrhage was 2.21.
• Hypertension was the most important risk factor.
• Stroke represented 1.2% of total deaths in India.
Epidemiology of stroke in India, Tapas Kumar
Neurology Asia 2006; 11 : 1 – 4

5. Stroke types and incidence:

6. Up to 80% of strokes are preventable!
National Stroke Association developed
the following guidelines to help people reduce their
risk for stroke…

7. Etiology
• Complication of several disorders
• Atherosclerosis – most common.
• Hypertension, smoking, diabetes.
• Heart disease – Atrial fibrillation.
• Other:
– Trauma – fat embolism
– Tumor, Infection

8. Risk Factors
• Heart disease
• Arrhythmias
• Diabetes Mellitus
• Smoking
• Obesity
• Transient ischemic attacks (TIA’s)

9. Pathophysiology - Stroke
Ischaemic cascade
 Ischaemic brain injury results from a cascade
 Starts with energy depletion leading to cell death
 Reduced blood supply causes starving of neurons
 Failure of mitochondria to produce ATP
 ATP dependent ion channels stop functioning
 Neurons depolarize,allowing excess entry of calcium and
sodium
 Excess glutamate release from synaptic terminals

10. Pathophysiology- Stroke
 Excess glutamate causes neurotoxicity
 Release of inflammatory substances from clot causes cell
membrane damage
 Free radicals produced by membrane lipid degradation and
mitochondrial injury
 Free radicals cause destruction of cell membrane & other
vital functions of cell

11. Pathophysiology- stroke

12. Pathophysiology
Neurons in the penumbra may
benefit from neuroprotection
before and after reperfusion
Reperfusion-induced oxidative
stress is accompanied by
deterioration of brain
Mitochondria1
Mediators of inflammation,
cytokines, such as platelet-
activating factor, interleukin-1(IL-
1), and tumor necrosis factor β, are
produced by injured brain cells2
Nitric oxide and oxidative stress are
linked to DNA damage and
activation of poly(ADPribose)
polymerase, a nuclear enzyme that
facilitates DNA repair and regulates
transcription3
1. Schild L, FEBS J. 2005;272(14):3593-601. 2. Dirnagl U, Trends Neurosci. 1999;22(9):391-7.
3. Lo EH, Nat Rev Neurosci. 2003;4(5):399-415.

13. Pathophysiology
• Cell damage leads to cell death
There is evidence that free radicals
and peroxynitrate can cause cell
damage1
• The important role of oxygen
freeradicals in cell damage
associated with stroke is
underscored by the fact that even
delayed treatment with free-radical
scavengers can be effective in
experimental focal cerebral
ischemia2
• In milder ischemic injury, cell death
resembles apoptosis (cell suicide),
particularly within the ischemic
1. Lipton P. Ischemic cell death in brain neurons. Physiological Reviews. Oct 1999;
vol. 79; 1431-1568. 2. Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke:
an integrated view. Trends Neurosci. 1999;22(9):391-7.

14. Immediate Treatment Options
Thrombolysis (tPA)
Aspirin
Antiplatelet agents
Fluids
“Blood Thinner” (heparin)
Neuroprotection: new option

15. Management of ischaemic stroke
• Stroke treatment shown rapid advances over last decade or
so
• Proven therapies include IV thrombolytics, use of aspirin
within 48 hrs and decompressive surgery for malignant MCA
infarction1
• Secondary prevention measures include antiplatelets,
anticoagulants, cholesterol reduction1
Rapid diagnosis, implementation of early preventive
treatment, early recognition of complications and
mobilization improve overall outcomes2
1. .Donnan GA, Fisher M, et al, Lancet 2008;371:1612-23
2. Brainin M, Teuschl Y, et al, Lancet Neurol 2007;6:533-61,

16. Intravenous thrombolysis
A Potent Weapon
• Intravenous thrombolysis with rtPA within 3 hrs of symptom
onset, currently approved for management of acute
ischaemic stroke
• It improves rates of favorable outcome
• Patients with mild to moderate strokes, younger persons
and those treated very early have best chances for
favourable outcome
P. N. Sylaja,Ann Indian Acad Neurol 2008;11:S24-S29

17. Intravenous thrombolysis
Limitations
• Small percentage of patients receive rtPA
• Narrow inclusion criteria within 3 hrs and multiple exclusion
limits the use of rtPA
• IV rtPA given alone produces recanalization in about 50% of
patients*
• Major hindrance to thrombolytic therapy is delay in patients
reaching hospital
• Healthcare infrastructure poor in rural areas
• Access to and affordability of investigation and treatment
are major concern
P. N. Sylaja,Ann Indian Acad Neurol 2008;11:S24-S29
* - Jose Suarez, Ann Indian Acad Neurol 2008;11:S30-38

18. Intra-arterial thrombolysis
Alternative/ Additional approach
• Alternative approaches to IV thrombolytic administration
have been explored
• IA rtPA or streptokinase or a combination of IV rtPA within 3
hrs and followed by IA rtPA are being used
• Therapeutic time window is expanded
• However, time to treatment for IA thrombolysis is longer
compared to IV
• Limitations: Need to assemble angiography team, confirm
occlusion, risk of invasive technique and also cost of
treatment
Jose Suarez, Ann Indian Acad Neurol 2008;11:S30-38

19. Infarct related edema
• Patients with large cortical or cerebellar infarctions are at high
risk of developing malignant cytotoxic edema
• Peak of brain edema typically occurs at day 2 to 7, but can
occur as late as day 14
• Medical treatment includes mannitol or hypertonic saline
• However, the anti-edematous effect of these agents are based
on osmosis principle only
David S, Stephan M, Clin Chest Med 30 (2009) 103-122

20. Neuroprotection in Stroke

21. Neuroprotection
• Neuroprotection is the mechanisms and strategies used to
protect against neuronal injury or degeneration in the Central
Nervous System (CNS) following acute disorders (e.g. stroke
or nervous system injury/trauma) or as a result of chronic
neurodegenerative diseases (e.g. Parkinson's, Alzheimer's,
Multiple Sclerosis).

22. ISCHEMIC PENUMBRA
• In the area of ischemia, there is a CENTRAL CORE with
marked reduction in CBF and a surrounding area of marginal
blood flow called the ‘ISCHEMIC PENUMBRA’.
• Ischaemic penumbra is “ischaemic tissue which is functionally
impaired and is at risk of infarction and has the potential to
be salvaged by reperfusion and/or other strategies.
• The ischemic area becomes perfusion dependent and any
decrease in systemic blood pressure can extend the area of
ischemia and infarction. In the penumbra, there is a
moderate ischemia.
CORE ISCHEMIC PENUMBRA
AREA (CBF ~ 25 –
(CBF<25% OF 50% OF
NORMAL NORMAL)

23. The penumbral concept
(1) penumbral tissue is an area of hypoperfused, abnormal
tissue with physiological and biochemical characteristics, or
both, consistent with cellular dysfunction but not cellular
death;
(2) the tissue is within the same ischemic territory as the infarct
core;
(3) the tissue can either survive or progress to necrosis; and
(4) salvage of the tissue is associated with better clinical
outcome.
If it is not salvaged this tissue is progressively recruited into the
infarct core which will expand with time into the maximal
volume originally at risk”
Lancet 2009; 8: 261-69

24. Neuronal protective agents
• Any agent or drug that protects the brain from secondary
injury caused by stroke.

25. NEUROPROTECTANTS
 Hypothermia , powerful neuroprotective option but not
well studied in stroke treatment
 Nimodipine, several studies regarding nimodipine in
stroke, with some confliciting results.
• NMDA receptor antagonists : e.g. : Dextrorphan, Selfotel
(Higher mortality in selfotel group at 30 days (p<.05),
and more behavioral effects, Stroke 2000;31(2):347-54)
• Nitric oxide synthetase inhibitor: e.g : Lubeluzole, poor
efficacy as measured by barthel index, Stroke
1997;28:2338-2346
• Anti-adhesion antibodies : e.g. : Enlimomab (mortality
and Rankin score worse in enlimomab administered
patients, Neurology 1997;48(Supp) A270
• Above agents failed to show satisfactory results (serious
adverse effects and lack of efficacy) except
• NEURONAL MEMBRANE STABILIZERS : Citicholine
• FREE RADICAL SCAVENGERS : EDARAVONE

26. Role of Edaravone
in the management of
Acute Ischaemic Stroke

27. Rationale for neuroprotection
• Free radicals play crucial role in ischaemic brain injury
• Exacerbate membrane damage through peroxidation of
unsaturated fatty acids leading to neuronal death and brain
edema
• Physiological systems involved in removal of free radicals are
impaired and formation of free radicals is further increased
Scavenging free radicals and prevention of
lipid peroxidation can directly suppress
brain edema
Hiroshi Yoshida, hidekatsu Yanai, et al, CNS Drugs Reviews, Vol 12, Number 1, pp 9-20, 2006

28. Neuroprotection: Role of Edaravone
• Edaravone , a novel free radical scavenger protects neurons by
inhibiting vascular endothelial injury and by ameliorating
neuronal damage caused by brain edema
• Edaravone inhibits both nonenzymatic lipid peroxidation and
lipooxygenase pathway
• Potent antioxidant effects against ischaemia/reperfusion-
induced vascular endothelial cell injury, delays neuronal death,
brain edema and consequently lessens the neurological deficits
Hiroshi Yoshida, hidekatsu Yanai, et al, CNS Drugs Reviews, Vol 12, Number 1, pp 9-20, 2006

29. Neuroprotection: Role of Edaravone
Cerebral ischaemia Reperfusion
Activation of arachidonic Excessive inflow
cascade of oxygen
Phospholipase A2
Edaravone
H2O2
Free radical production Free radical production
OH- Hydroxyl O2-(superoxide)
Vascular endothelial Cell membrane Neurocyte
injury injury injury
Deterioration of cerebral infarction with exacerbated symptoms
Increased infarct Neurological Delayed neutrocytes
Brain edema
volume symptoms necrosis
Adapted from Hiroshi Yoshida, hidekatsu Yanai, et al, CNS Drugs Reviews, Vol 12, Number 1, pp 9-20, 2006

30. Neuroprotective effects of Edaravone in
cerebrovascular injury
• Edaravone can inhibit peroxidation of membrane lipids
initiated by water soluble and lipid solouble radicals
• Edaravone is a low molecular wt radical scavenger which
has a BBB permeability of 60% unlike Superoxide
dismutase which has a difficulty in entering the BBB
• Edaravone, after administration eliminates highly toxic
hydroxyl radicals, preferentially in ischemic penumbra
• Edaravone does not affect blood coagulation, platelet
aggregation, fibrinolysis or bleeding time, hence there is
no risk of additional bleeding
H. Tohgi, K. Kogure, et al, Cerebrovascular Dis 2003;15:222-229

31. Edaravone in acute brain infarction
 A multicenter, randomized, placebo controlled, double blind
trial conducted to verify its therapeutic efficacy in ischaemic
stroke
 N=250 (both thrombotic and embolic types), Edaravone - 125
patients; Placebo - 125 patients
 Edaravone given within 72 hrs of onset of stroke at the dose
of 30 mg, BID for 14 days
 Fibrinolytic agents (urokinase, rtPA, ozagrel and citicoline)
avoided throughout the study
H. Tohgi, K. Kogure, et al, Cerebrovascular Dis 2003;15:222-229

32. Edaravone in acute brain infarction
 Functional outcome measured at 3 months or at discharge
within three months using Modified Rankin Scale
 Additionally outcome data collected at 3, 6 and 12 months
 Results – Significant difference between two groups in favour
of Edaravone group in terms of functional outcome (p=0.03)
 Improvement in functional outcome sustained for relatively
longer time
 Better clinical outcome when given within 24 hrs of symptom
onset
H. Tohgi, K. Kogure, et al, Cerebrovascular Dis 2003;15:222-229

33. Effect of novel free radical scavenger, edaravone
on acute brain infarction
N=250 (both thrombotic
and embolic types)
,edaravone (30 mg, BID
76
for 14 days) given to 125
52
patients and placebo to
125
Edaravone : beneficial in combination therapy with fibrinolytic agents , leading to
expansion of therapeutic time window
H. Tohgi, K. Kogure, et al, Cerebrovascular Dis 2003;15:222-229

34. Edaravone in internal carotid artery
occlusion
 Therapeutic effect of Edaravone was evaluated in patients with
severe carotid artery stroke
 Patients (baseline NIHSS score =/> 15) were treated with
Edaravone for 14 days (n=30) and compared with historical
control cohort of similar patients (n=31)*
 Infarct volume on CT performed on day 2 in Edaravone group
were smaller than those without Edaravone (p<0.02)
 Hemorrhagic transformation of infarct on day 2 was less severe
in Edaravone group compared to without it (p<0.03)
*10% Glycerol to all, rtPA, Heparin at discretion
Kazunori Toyoda, Kenichiro Fujii,et al, Journal of the Neurological Sciences 221 (2004) 11-17

35. Edaravone in patients with internal carotid artery
occlusion
Edaravone was associated with delayed evolution of
infarcts and edema in patients with severe carotid
artery stroke and decreased mortality during acute
stage
Kazunori Toyoda, Kenichiro Fujii,et al, Journal of the Neurological Sciences 221 (2004) 11-17

36. Effect of Edaravone on ischaemic cerebral
edema assessed by MRI
 T2-weigted MRI can both visualize and quantify vasogenic
edema therefore it is an important method to assess efficacy of
therapies for stroke
 Antiedema effect of Edaravone was evaluated in patients with
extensive hemispheric ischaemic stroke
 T2 relaxation time was calculated in the infarct core, boundary
zone of infarct and T2 mapping was performed before and after
edaravone treatment
 Edaravone administration significantly decreased the mean T 2 –
relaxation time in the boundary zone of infarct (p=0.008)
 Conclusion – Edaravone can salvage the boundary zone of the
infarct and is a useful cytoprotective antiedema agent
Satoshi Suda , Hironaka Igarashi, et al, Neurol. Med Chir (Tokyo) 47, 197-202,2007

37. Edaravone diminishes free radicals from
circulating neutrophils in patients with
ischaemic stroke
 Study investigated effects of Edaravone on oxidative stress
markers of circulating neutrophils in patients with ischaemic
stroke
 Edaravone 30mg – 21 patients; Ozagrel 40mg (thromboxane A2
synthase inhibitor) – 19 patients
 Intracellular reactive oxygen species of neutrophils were
measured by chemiluminescence assay
 Edaravone significantly decreased the intracellular reactive
oxygen species of neutrophils
 Conclusion – Reduction of intracellular reactive oxygen species
and suppression of superoxide production may be responsible
for clinical efficacy of edaravone in patients with ischaemic
stroke
Hitoshi Aizawa, Yoshiniro Makita, et al, Internal Medicine , doi:10.2169/internal medicine . 45.1491

38. Efficacy of edaravone for the treatment of
Acute Lacunar Infarction
 Retrospective analysis of 70 patients with lacunar infarct
admitted within 24 hrs of stroke onset, who were given
Edaravone treatment in addition to routine treatment
 Clinical status at baseline assessed using NIHSS score
 Modified Rankin Scale (MRS) used to assess clinical outcome at 3
months (good outcome defined as MRS =/<2)
 Routine treatment was continued (IV heparin, glycerol, ozagrel
sodium, oral antiplatelet drugs like aspirin, ticlopidine)
M. Mishira, Y. Komaba, et al , Neurol Med Chir (Tokyo) 45, 344-348, 2005

39. Efficacy of edaravone for the treatment of
Acute Lacunar Infarction
 Edaravone added to conventional treatment (14 days)
 70% of patients had a good outcome with MRS score =/<2
 Higher baseline NIHSS score and higher age adversely
affected outcome
 After adjustment for this effect, the results still indicated that
Edaravone significantly improved functional outcome
Conclusion – Edaravone is a promising free radical
scavenger for the treatment of patients with acute
lacunar stroke
M. Mishira, Y. Komaba, et al , Neurol Med Chir (Tokyo) 45, 344-348, 2005

40. Edaravone in patients with traumatic brain
injury (TBI)
 Lipid peroxidation caused by reactive oxygen species is
involved in traumatic brain injury (TBI)
 Therapeutic strategy for TBI involves control of lipid
peroxidation
 Present study used in vitro & ex vivo techniques to study
whether Edaravone can scavenge alkoxyl radicals (OR-)
 Jugular venous blood collected from 17 TBI patients
immediately before and 20 min after Edaravone
administration
Keneji Dohi, Kazue satoh, et al, Journal of Neurotrauma, Volume 23, Number 11, 2006, pp. 1591-1599

41. Edaravone in patients with traumatic
brain injury (TBI)
 Higher OR- levels in blood of untreated patients than in
normal control
 Treatment with edaravone suppresses OR- level by 24.6%
Conclusion – Edaravone may be useful for preventing lipid
peroxidation in patients with TBI
Keneji Dohi, Kazue satoh, et al, Journal of Neurotrauma, Volume 23, Number 11, 2006, pp. 1591-1599

42. Diminishes Free Radicals from Circulating
Neutrophils in Ischemic Brain Attack
Amount of superoxide
produced by neutrophils
stimulated byphorbol
myristate acetat (PMA)
before and after treatment
with edaravone or ozagrel
The superoxide
production by neutrophils
decreased after treatment
with edaravone in patients
with ischemic brain attack
(Wilcoxon
test, p=0.001)
2006 The Japanese Society of Internal Medicine

43. Edaravone in Acute Myocardial Infarct
IV Inj. Edaravone 30 mg for 10 min before myocardial reperfusion decreased
Serum CK-MB and improved left ventricular ejection fraction in pts with
Acute MI
Recent Patents on Cardiovascular Drug Discovery, 2006, Vol. 1, No. 1 89

44. Clinical Evidence in CEA
• Pretreatment with edaravone can prevent development of
cognitive impairment after carotid endarterectomy (CEA).
|Surg Neurol. 2005 Oct;64(4):309-13
• In patients with cortical infarcts, edaravone reduced oxidative
damage, thereby limiting the degree of brain damage, as
measured by plasma biomarkers.
Free Radic Biol Med. 2005 Oct 15;39(8):1109-16.

45. Edaravone – new clinical data
• Edaravone dose-dependently increases rehabilitation gain according to DeltaFIM-M
and DeltaBI scores in patients with cardioembolic stroke. Clin Drug Investig.
2010;30(3):143-55
• Edaravone significantly reduced oxidative cell death in both neuronal cells and
primary rat astrocytes and thus protects component of neurovascular unit. Brain
Res. 2010 Jan 11;1307:22-7
• Edaravone inhibited production of free radicals known to induce neuronal
degeneration and cell death after brain injury, with the potential to differentiate
into neurons and glia around the area damaged by TBI. Neurotox Res. 2009
Nov;16(4):378-89.

46. Citicoline in Stroke

47. Rationale for citicoline
• Precursor of phosphatidylcholine, a vital component of
neuronal membrane.
• Reduces the dysfunction of BBB, decreases cerebral
edema, activates cerebral energy metabolism.
• Provides the cytidine & choline. Choline is essential for
the synthesis of Acetylcholine (the cholinergic
neurotransmitter)
• Inhibits Phospholipase A2 thereby :
– preserves neuronal membrane integrity
– promotes neuronal membrane repair
– inhibits the release of free fatty acids & ARA
– inhibits free radical damage
J our Of Neurochemistry, 2002,80,12-23
Jour Of NeuroSci Res, 2002, 70:133-9

48. Effect of citicoline
A. Normal synthesis of
phophotidylcholine
B. Effect of Ischemia
C. Reversal of
increased FFA with
citicoline

49. Clinical efficacy
 Since 1980’s , 13 trials have been done with citicoline in stroke
management
 9 in Europe & Japan, 4 in the U.S.
 European trials showed citicoline improved global & neurological
function , earlier motor & cognitive recovery
 Large multicenter studies in Japan showed citicoline improved global
outcome rating scale
 However, subsequent analysis showed citicoline treatment for 6
weeks improved overall recovery at week 12

50. Citicoline in acute cerebrovascular disease
 A comparative, randomized study evaluated efficacy of citicoline
 N = 80 (>65 years, in acute phase of ischemic stroke)
 Mild to moderate impaired consciousness with a score of >10 on GCS
(Glasgow coma scale)
 Equal no. of patients received citicoline & control
 Dose – Citicoline 1g/8hrs as a daily dose for 10 days
 Citicoline showed significant improvement in GCS score (12.55 to
13.85)
Julio J et al, Citicoline: Pharmacological and Clinical Review, 2006 Update,Methods Find Exp Clin
Pharmacol 2006, 28(Suppl. B): 1
.

51. Citicoline in acute cerebrovascular disease
(Significant improvement in GCS scores)
Julio J et al, Citicoline: Pharmacological and Clinical Review, 2006
Update,Methods Find Exp Clin Pharmacol 2006, 28(Suppl. B): 1
.

52. Citicoline in acute cerebrovascular
disease
N=100
Citicoline
500mg/day
(oral) for 6
weeks.
Placebo citicoline
Significant decrease in lesion volume by 17.2 cc
compared to placebo by 6.9 cc at 12 weeks as
measured by MRI.
Expert Opinion on Pharmacotherapy, Volume 10, Number 5, April 2009 , pp.
839-846(8)

53. Citicoline in HEAD INJURY
• Accelerates the recovery of neurological symptoms
• Accelerates the resolution of brain edema on CT
• Reduces hospital stay
• Better quality in the evolution
• Improves the global functional outcome
• Reduces the post-concussional syndrome

54. Citicoline in head trauma
A double blind ,placebo controlled study involving 60 patients
with severs head trauma
 Citicoline 750mg/day (IV) – 6 days
 Citicoline 750mg/day (IM) – 20 days
 Clinical evaluation was continued for upto 6 months.
Observations
 Response to painful stimuli superior in citicoline group at
day 15 compared to placebo (p<0.01)
 Greater recovery from neurological deficits observed in
citicoline group
 Autonomous ambulation was seen in 84% of patients in
citicoline grp compared to 62.5 in placebo at 120 days
 Difference statistically significant from day 60 (p<0.01)
Julio J et al, Citicoline: Pharmacological and Clinical Review, 2006
Update,Methods Find Exp Clin Pharmacol 2006, 28(Suppl. B): 1
.

55. Citicoline in head trauma
N=100
p=<0.05
(Number of patients showing normalization of state of consciousness
in relation to time and treatment)
Response to painful stimuli superior in citicoline group at day 15
Greater recovery from neurological deficits and Autonomous ambulation was
seen in 84% of patients in citicoline grp

56. Citicoline in head trauma
(Significantly less % of patients showing neurological
complications with citicoline

58. Clinical data –citicoline in stroke
 In a double blind, multicenter (63 Japanese Academic centers),
placebo controlled study in 272 patients with stroke given citicoline
1g/day/14 days (IV) -- effective and safe drug for the treatment of
acute cerebral infarction. (Stroke. 1988;19:211-216)
• A multicenter, DB controlled trial, conducted by the Citicoline Stroke
Study Group (N=259) examined the effects of oral citicoline(500mg;
1,000 mg; or 2,000 mg) after 12 weeks showed that citicoline pts
have twice the chance of stroke recovery compared to patients on
placebo. (Neurology 1997;49:671-78)

59. Clinical data –citicoline in stroke
 Meta-analysis of 4 large trial done in the U.S.-- citicoline
treatment showed significant improvement in patients who
had achieved an almost complete recovery at 3 months in
daily routine activity and functional activity and is more
effective in patients with moderate to severe acute ischaemic
stroke (Stroke. 2002;33:2850-2857)
• Similarly citicoline found effective if combined with
thromlytic agents in stroke .

60. Citicoline –New data
• Citicoline in Stroke – citicoline administered within 24h
after moderate to severe stroke is safe and increases the
probability of recovery within 3 months- Exp Opin Pharmthr
Apr 2009
• Citicoline in Brain Injury CORBIT Trial – Ongoing to
complete enrollment by Aug 2010 - J Neurotrauma Dec
2009
• Citicoline widely available agent in Neuroprotection and
repair –Meta-analysis of 10 trials enrolling 2279 pts
suggests citicoline treatment reduced frequency of death
and disability. (Rev Neurol Dis 2008)

61. Citicoline in Mild Cognitive Impairment
 Mild cognitive impairment (MCI) involves slight loss of
memory without significant effect on other cognitive
functions
 Approximately 12% of patients with MCI advance annually
to develop Alzheimer’s disease
 Meta analysis of 12 clinical trials show
 Citicoline improves memory
 Behavior
 Overall clinical improvement
Hence citicoline may prove effective in age related cognitive
decline that may be a precursor of dementia

62. Citicoline in Parkinson’s disease
 Citicoline shown dopamine agonist properties
 Citicoline 600mg/day/10 days (IV) shown improvement in
bradykinesia, rigidity & tremors
 Allows reduction of levodopa ,hence reduces levodopa related
adverse effects
 Discontinuation of citicoline worsened symptoms
• New strategies in the management of Parkinson’s disease
using a phospholipid precursor (CDP-choline) improvements
in bradykinesia and rigidity.
(Neuropsychobiology 1982;8:289-296.)

63. Thank You