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1.  Neuroprotective Properties of Citicoline: Facts, Doubts and Unresolved Issues 
CNS Drugs  2014;28(3):185-193.
Citicoline is the generic name of the pharmaceutical substance that chemically is cytidine-5′-diphosphocholine (CDP-choline), which is identical to the natural intracellular precursor of phospholipid phosphatidylcholine. Following injection or ingestion, citicoline is believed to undergo quick hydrolysis and dephosphorylation to yield cytidine and choline, which then enter the brain separately and are used to resynthesize CDP-choline inside brain cells. Neuroprotective activity of citicoline has been repeatedly shown in preclinical models of brain ischaemia and trauma, but two recent, large, pivotal clinical trials have revealed no benefits in ischaemic stroke and traumatic brain injury. However, the substance seems to be beneficial in some slowly advancing neurodegenerative disorders such as glaucoma and mild vascular cognitive impairment. This paper critically discusses issues related to the clinical pharmacology of citicoline, including its pharmacokinetics/biotransformation and pharmacodynamics/mode of action. It is concluded that at present, there is no adequate description of the mechanism(s) of the pharmacological actions of this substance. The possibility should be considered and tested that, in spite of apparently fast catabolism, the intact citicoline molecule or the phosphorylated intermediate products of its hydrolysis, cytidine monophosphate and phosphocholine, are pharmacologically active.
doi:10.1007/s40263-014-0144-8
PMCID: PMC3933742  PMID: 24504829
2.  Update in Intracerebral Hemorrhage 
The Neurohospitalist  2011;1(3):148-159.
Spontaneous, nontraumatic intracerebral hemorrhage (ICH) is defined as bleeding within the brain parenchyma. Intracranial hemorrhage includes bleeding within the cranial vault and encompasses ICH, subdural hematoma, epidural bleeds, and subarachnoid hemorrhage (SAH). This review will focus only on ICH. This stroke subtype accounts for about 10% of all strokes. The hematoma locations are deep or ganglionic, lobar, cerebellar, and brain stem in descending order of frequency. Intracerebral hemorrhage occurs twice as common as SAH and is equally as deadly. Risk factors for ICH include hypertension, cerebral amyloid angiopathy, advanced age, antithrombotic therapy and history of cerebrovascular disease. The clinical presentation is “stroke like” with sudden onset of focal neurological deficits. Noncontrast head computerized tomography (CT) scan is the standard diagnostic tool. However, newer neuroimaging techniques have improved the diagnostic yield in terms of underlying pathophysiology and may aid in prognosis. Intracerebral hemorrhage is a neurological emergency. Medical care begins with stabilization of airway, breathing function, and circulation (ABCs), followed by specific measures aimed to decrease secondary neurological damage and to prevent both medical and neurological complications. Reversal of coagulopathy when present is of the essence. Blood pressure management can be key and continues as an area of debate and ongoing research. Surgical evacuation of ICH is of unproven benefit though a subset of well-selected patients may have improved outcomes. Ventriculostomy and intracranial pressure (ICP) monitoring are interventions also used in this patient population. To date, hemostatic medications and neuroprotectants have failed to result in clinical improvement. A multidisciplinary approach is recommended, with participation of vascular neurology, vascular neurosurgery, critical care, and rehabilitation medicine as the main players.
doi:10.1177/1941875211409050
PMCID: PMC3726132  PMID: 23983850
intracerebral hemorrhage; diagnosis; treatment; prognosis; surgery
3.  Efficacy and Safety of Panax notoginseng Saponin Therapy for Acute Intracerebral Hemorrhage, Meta-Analysis, and Mini Review of Potential Mechanisms of Action 
Intracranial/intracerebral hemorrhage (ICH) is a leading cause of death and disability in people with traumatic brain injury (TBI) and stroke. No proven drug is available for ICH. Panax notoginseng (total saponin extraction, PNS) is one of the most valuable herb medicines for stroke and cerebralvascular disorders in China. We searched for randomized controlled clinical trials (RCTs) involving PNS injection to treat cerebral hemorrhage for meta-analysis from various databases including the Chinese Stroke Trials Register, the trials register of the Cochrane Complementary Medicine Field, the Cochrane Central Register of Controlled Trials, MEDLINE, Chinese BioMedical disk, and China Doctorate/Master Dissertations Databases. The quality of the eligible trials was assessed by Jadad’s scale. Twenty (20) of the 24 identified randomized controlled trials matched the inclusive criteria including 984 ICH patients with PNS injection and 907 ICH patients with current treatment (CT). Compared to the CT groups, PNS-treated patients showed better outcomes in the effectiveness rate (ER), neurological deficit score, intracranial hematoma volume, intracerebral edema volume, Barthel index, the number of patients died, and incidence of adverse events. Conclusion: PNS injection is superior to CT for acute ICH. A review of the literature shows that PNS may exert multiple protective mechanisms against ICH-induced brain damage including hemostasis, anti-coagulation, anti-thromboembolism, cerebral vasodilation, invigorated blood dynamics, anti-inflammation, antioxidation, and anti-hyperglycemic effects. Since vitamin C and other brain cell activators (BCA) that are not considered common practice were also used as parts of the CT in several trials, potential PNS and BCA interactions could exist that may have made the effect of PNS therapy less or more impressive than by PNS therapy alone. Future PNS trials with and without the inclusion of such controversial BCAs as part of the CT could clarify the situation. As PNS has a long clinical track record in Asia, it could potentially become a therapy option to treat ICH in the US and Europe. Further clinical trials with better experimental design could determine the long-term effects of PNS treatment for TBI and stroke.
doi:10.3389/fneur.2014.00274
PMCID: PMC4288044  PMID: 25620952
notoginsenosides; botanical medicine; nutraceuticals; TBI and stroke recovery; randomized controlled clinical trials; hemostasis; anti-coagulation; pharmacological mechanisms
4.  A critical appraisal of experimental intracerebral hemorrhage research 
The likelihood of translating therapeutic interventions for stroke rests on the quality of preclinical science. Given the limited success of putative treatments for ischemic stroke and the reasons put forth to explain it, we sought to determine whether such problems hamper progress for intracerebral hemorrhage (ICH). Approximately 10% to 20% of strokes result from an ICH, which results in considerable disability and high mortality. Several animal models reproduce ICH and its underlying pathophysiology, and these models have been widely used to evaluate treatments. As yet, however, none has successfully translated. In this review, we focus on rodent models of ICH, highlighting differences among them (e.g., pathophysiology), issues with experimental design and analysis, and choice of end points. A Pub Med search for experimental ICH (years: 2007 to 31 July 2011) found 121 papers. Of these, 84% tested neuroprotectants, 11% tested stem cell therapies, and 5% tested rehabilitation therapies. We reviewed these to examine study quality (e.g., use of blinding procedures) and choice of end points (e.g., behavioral testing). Not surprisingly, the problems that have plagued the ischemia field are also prevalent in ICH literature. Based on these data, several recommendations are put forth to facilitate progress in identifying effective treatments for ICH.
doi:10.1038/jcbfm.2012.8
PMCID: PMC3318157  PMID: 22293989
animal models; intracerebral hemorrhage; neuroprotection; rehabilitation; stem cells
5.  Utility of Early MRI in the Diagnosis and Management of Acute Spontaneous Intracerebral Hemorrhage 
Background
The optimal diagnostic evaluation for spontaneous intracerebral hemorrhage (ICH) remains controversial. In this retrospective study, we assessed the utility of early magnetic resonance imaging (MRI) in ICH diagnosis and management.
Methods
Eighty-nine (72%) of 123 patients with spontaneous ICH underwent a brain CT and MRI within 30 days of ICH onset. Seventy patients with a mean age of 62 ± 15 years were included. A stroke neurologist and a general neurologist, each blinded to the final diagnosis, independently reviewed the admission data and the initial head CT and then assigned a presumed ICH cause under 1 of 9 categories. ICH cause was potentially modified after subsequent MRI review. The final ‘gold standard’ ICH etiology was determined after review of the complete medical record by an independent investigator. Change in diagnostic category and confidence and the potential impact on patient management were systematically recorded.
Results
Mean time to MRI was 3 ± 5 days. Final ICH diagnosis was hypertension or cerebral amyloid angiopathy (CAA) in 50% of patients. After MRI review the stroke neurologist changed diagnostic category in 14%, diagnostic confidence in an additional 23% and management in 20%, and the general neurologist did so in 19, 21 and 21% of patients, respectively. MRI yield was highest in ICH secondary to ischemic stroke, CAA, vascular malformations and neoplasms, and did not differ by age, history of hypertension, hematoma location or the presence of intraventricular hemorrhage.
Conclusions
The results of this study suggest potential additive clinical benefit of early MRI in patients with spontaneous ICH.
doi:10.1159/000316892
PMCID: PMC2992640  PMID: 20733299
Cerebral hemorrhage; Magnetic resonance imaging; Diagnostic imaging
6.  Location and Characteristics of Warfarin Associated Intracranial Hemorrhage 
Objective
In the so-called primary intracerebral hemorrhage (ICH), lobar and deep ICH were mainly due to cerebral amyloid angiopathy and deep perforating arterial disease. Our aim was to identify specifics of warfarin associated ICH (WAICH) and to focus on differences in susceptibility to warfarin according to the underlying vasculopathies, expressed by ICH location.
Materials and Methods
We identified all subjects aged ≥ 18 years who were admitted with primary ICH between January 1, 2007 and September 30, 2012. We retrospectively collected demographic characteristics, the presence of vascular risk factors and pre-ICH medication by chart reviews. We categorized ICH into four types according to location: lobar, deep, posterior fossa, and undetermined. We investigated characteristics (including hematoma volume and expansion) of ICH according to the location of ICH.
Results
WAICH accounted for 35 patients (5.6%) of 622 ICH cases. In WAICH, 13 patients (37.1%) had lobar ICH and 22 patients (60.0%) had non-lobar ICH. Compared to other locations of ICH, lobar ICH showed an excess risk of WAICH (OR 2.53, 95% CI 1.03-6.21, p = 0.042). The predictors of lobar location of ICH were warfarin (OR 2.29, 95% CI 1.05-5.04, p = 0.038) and diabetes mellitus (DM) (OR 0.54, 95% CI 0.29-0.98, p = 0.044). The lobar location of ICH showed significant association with larger hematoma volume (p = 0.001) and high ratio of hematoma expansion (p = 0.037) compared with other locations of ICH.
Conclusion
In our study, warfarin showed significant association with lobar ICH and it caused larger hematoma volume and more expansion of hematoma in lobar ICH.
doi:10.7461/jcen.2014.16.3.184
PMCID: PMC4205243  PMID: 25340019
Warfarin; Cerebral amyloid angiopathy; Intracerebral hemorrhage
7.  Putative Role of Prostaglandin Receptor in Intracerebral Hemorrhage 
Each year, approximately 795,000 people experience a new or recurrent stroke. Of all strokes, 84% are ischemic, 13% are intracerebral hemorrhage (ICH) strokes, and 3% are subarachnoid hemorrhage strokes. Despite the decreased incidence of ischemic stroke, there has been no change in the incidence of hemorrhagic stroke in the last decade. ICH is a devastating disease 37–38% of patients between the ages of 45 and 64 die within 30 days. In an effort to prevent ischemic and hemorrhagic strokes we and others have been studying the role of prostaglandins and their receptors. Prostaglandins are bioactive lipids derived from the metabolism of arachidonic acid. They sustain homeostatic functions and mediate pathogenic mechanisms, including the inflammatory response. Most prostaglandins are produced from specific enzymes and act upon cells via distinct G-protein coupled receptors. The presence of multiple prostaglandin receptors cross-reactivity and coupling to different signal transduction pathways allow differentiated cells to respond to prostaglandins in a unique manner. Due to the number of prostaglandin receptors, prostaglandin-dependent signaling can function either to promote neuronal survival or injury following acute excitotoxicity, hypoxia, and stress induced by ICH. To better understand the mechanisms of neuronal survival and neurotoxicity mediated by prostaglandin receptors, it is essential to understand downstream signaling. Several groups including ours have discovered unique roles for prostaglandin receptors in rodent models of ischemic stroke, excitotoxicity, and Alzheimer disease, highlighting the emerging role of prostaglandin receptor signaling in hemorrhagic stroke with a focus on cyclic-adenosine monophosphate and calcium (Ca2+) signaling. We review current ICH data and discuss future directions notably on prostaglandin receptors, which may lead to the development of unique therapeutic targets against hemorrhagic stroke and brain injuries alike.
doi:10.3389/fneur.2012.00145
PMCID: PMC3477820  PMID: 23097645
brain; stroke; inflammation; GPCR; therapy; neurodegenerative diseases
8.  Stroke management 
Clinical Evidence  2011;2011:0201.
Introduction
Stroke is the third most common cause of death in most developed countries. It is a worldwide problem; about 4.5 million people die from stroke each year. Stroke can occur at any age, but half of all strokes occur in people aged over 70 years. About 80% of all acute strokes are ischaemic, usually resulting from thrombotic or embolic occlusion of a cerebral artery. The remainder are caused either by intracerebral or subarachnoid haemorrhage.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of specialised care in people with acute stroke? What are the effects of medical treatment in people with acute ischaemic stroke? What are the effects of decompressive hemicraniectomy in acute ischaemic stroke? What are the effects of surgical evacuation for intracerebral haematomas? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 41 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: acute reduction in blood pressure, aspirin, evacuation (early surgical evacuation, or conservative treatment), decompressive hemicraniectomy, neuroprotective agents (calcium channel blockers, citicoline, gamma-aminobutyric acid agonists, glycine antagonists, lubeluzole, magnesium, N-methyl-D-aspartate antagonists), specialised stroke care, systemic anticoagulation (heparinoids, specific thrombin inhibitors, low molecular weight heparin, oral anticoagulants, unfractionated heparin), and thrombolysis.
Key Points
Stroke is characterised by rapidly developing clinical symptoms and signs of focal, and at times global, loss of cerebral function lasting over 24 hours or leading to death, with no apparent cause other than that of vascular origin. Ischaemic stroke (which accounts for about 80% of all acute strokes) is caused by vascular insufficiency (such as cerebrovascular thromboembolism) rather than haemorrhage.Stroke is the third most common cause of death in most developing countries, with about 4.5 million people worldwide dying from stroke each year.About 10% of all people with acute ischaemic strokes will die within 30 days of onset, and, of those who survive the acute event, about 50% will still experience some level of disability after 6 months.
Specialised stroke rehabilitation seems more effective than conventional care at reducing death and dependency after 1 year.
Aspirin effectively reduces death or dependency at 6 months when given within 48 hours of ischaemic stroke. Aspirin has a similar effectiveness to anticoagulants (unfractionated or low molecular weight heparin) in acute stroke, but a lower risk of intracranial and extracranial haemorrhage.
Thrombolysis (given within 3 hours of symptom onset) reduces death or dependency at 6 months in people with confirmed ischaemic stroke, but increases the risk of symptomatic haemorrhage. The reduction in death or dependency may not apply to streptokinase treatment.
Although there seems to be a direct link between blood pressure and risk of recurrent stroke, acute blood pressure lowering in acute ischaemic stroke may actually lead to increased cerebral ischaemia.
Neuroprotective drugs do not seem to be effective in reducing death or dependency in people with ischaemic stroke.
In younger people with malignant middle cerebral artery infarction, decompressive hemicraniectomy is an effective life-saving treatment.
In people with primary supratentorial haematomas, surgical evacuation may be more effective at reducing death or dependency. We found no high-quality evidence examining the effects of evacuation in people with infratentorial haematoma whose consciousness level is declining.
PMCID: PMC3217648  PMID: 21658301
9.  Acute and Delayed Protective Effects of Pharmacologically Induced Hypothermia in an Intracerebral Hemorrhage Stroke Model of Mice 
Neuroscience  2013;252:489-500.
Hemorrhagic stroke, including intracerebral hemorrhage (ICH), is a devastating subtype of stroke; yet, effective clinical treatment is very limited. Accumulating evidence has shown that mild to moderate hypothermia is a promising intervention for ischemic stroke and ICH. Current physical cooling methods, however, are less efficient and often impractical for acute ICH patients. The present investigation tested pharmacologically induced hypothermia (PIH) using the second generation neurotensin receptor (NTR) agonist HPI-201 (formerly known as ABS-201) in an adult mouse model with ICH. Acute or delayed administrations of HPI-201 (2 mg/kg bolus injection followed by 2 injections of 1 mg/kg, i.p.) were initiated at 1 or 24 hrs after ICH. HPI-201 induced mild hypothermia within 30 min and maintained body and brain temperatures at 32.7±0.4°C for at least 6 hrs without causing observable shivering. With the 1 hr delayed treatment, HPI-201-induced PIH significantly reduced ICH-induced cell death and brain edema compared to saline-treated ICH animals. When HPI-201-induced hypothermia was initiated 24 hrs after the onset of ICH, it still significantly attenuated brain edema, cell death and blood brain barrier breakdown. HPI-201 significantly decreased the expression of MMP-9, reduced caspase-3 activation, and increased Bcl-2 expression in the ICH brain. Moreover, ICH mice received 1-hr delayed HPI-201 treatment performed significantly better in the neurological behavior test 48 hrs after ICH. All together, these data suggest that systemic injection of HPI-201 is an effective hypothermic strategy that protects the brain from ICH injury with a wide therapeutic window. The protective effect of this PIH therapy is partially mediated through the alleviation of apoptosis and neurovascular damage. We suggest that pharmacological hypothermia using the newly developed neurotensin analogs is a promising therapeutic treatment for ICH.
doi:10.1016/j.neuroscience.2013.07.052
PMCID: PMC3961766  PMID: 23912033
Intracerebral hemorrhage; pharmacological hypothermia; PIH; neurotensin receptor; ABS-201; HPI-201
10.  Stroke management 
Clinical Evidence  2010;2010:0201.
Introduction
Stroke is the third most common cause of death in most developed countries. It is a worldwide problem; about 4.5 million people die from stroke each year. Stroke can occur at any age, but half of all strokes occur in people aged over 70 years. About 80% of all acute strokes are ischaemic, usually resulting from thrombotic or embolic occlusion of a cerebral artery. The remainder are caused either by intracerebral or subarachnoid haemorrhage.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of specialised care in people with acute stroke? What are the effects of medical treatment in people with acute ischaemic stroke? What are the effects of decompressive hemicraniectomy in acute ischaemic stroke? What are the effects of surgical evacuation for intracerebral haematomas? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 44 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: acute reduction in blood pressure, aspirin, evacuation (early surgical evacuation, or conservative treatment), decompressive hemicraniectomy, neuroprotective agents (calcium channel blockers, citicoline, gamma-aminobutyric acid agonists, glycine antagonists, lubeluzole, magnesium, N-methyl-D-aspartate antagonists), specialised stroke care, systemic anticoagulation (heparinoids, low or specific thrombin inhibitors, low molecular weight heparin, oral anticoagulants, unfractionated heparin), and thrombolysis.
Key Points
Stroke is characterised by rapidly developing clinical symptoms and signs of focal, and at times global, loss of cerebral function lasting over 24 hours or leading to death, with no apparent cause other than that of vascular origin. Ischaemic stroke (which accounts for about 80% of all acute strokes) is caused by vascular insufficiency (such as cerebrovascular thromboembolism) rather than haemorrhage.It is the third most common cause of death in most developing countries, with about 4.5 million people worldwide dying from stroke each year.About 10% of all people with acute ischaemic strokes will die within 30 days of onset, and, of those who survive the acute event, about 50% will still experience some level of disability after 6 months.
Specialised stroke rehabilitation seems more effective than conventional care at reducing death and dependency after 1 year.
Aspirin effectively reduces death or dependency at 6 months when given within 48 hours of ischaemic stroke. Aspirin has a similar effectiveness as anticoagulants (unfractionated or low molecular weight heparin), but a lower risk of intra- and extracranial haemorrhage.
Thrombolysis (given within 3 hours of symptom onset) reduces death or dependency at 6 months in people with confirmed ischaemic stroke, but increases the risk of symptomatic haemorrhage. The reduction in death or dependency may not apply to streptokinase treatment.
While there does seem to be a direct link between blood pressure and risk of recurrent stroke, acute blood pressure lowering in acute ischaemic stroke may actually lead to increased cerebral ischaemia.
Neuroprotective drugs do not seem to significantly reduce the risk of poor outcome (including death) or to improve outcome in people with ischaemic stroke.
In young people with malignant middle cerebral artery (MCA) infarction, decompressive hemicraniectomy is an effective life-saving treatment.
In people with primary supratentorial haematomas, surgical evacuation may be more effective at reducing death or dependency. We found no evidence examining the effects of evacuation in people with infratentorial haematoma whose consciousness level is declining.
PMCID: PMC2907612
11.  Predictors of outcome in childhood intracerebral hemorrhage: a prospective consecutive cohort study 
Background and Purpose
To describe features of children with intracerebral hemorrhage (ICH) and to determine predictors of short-term outcome in a single-center prospective cohort study.
Methods
Single-center prospective consecutive cohort study of spontaneous ICH in children age 1-18 years from January 2006 to June 2008. Exclusion criteria were inciting trauma; intracranial tumor; isolated epidural, subdural, intraventricular, or subarachnoid hemorrhage; hemorrhagic transformation of ischemic stroke; and cerebral sinovenous thrombosis. Hospitalization records were abstracted. Follow-up assessments included outcome scores using the Pediatric Stroke Outcome Measure (PSOM) and King's Outcome Scale for Childhood Head Injury (KOSCHI). ICH volumes and total brain volumes (TBV) were measured by manual tracing.
Results
Twenty-two patients, median age of 10.3 years (range 4.2-16.6 years), had presenting symptoms of headache in 77%, focal deficits 50%, altered mental status 50%, and seizures 41%. Vascular malformations caused hemorrhage in 91%. Surgical treatment (hematoma evacuation, lesion embolization or excision) was performed during acute hospitalization in 50%. One patient died acutely. At median follow-up of 3.5 months (range 0.3-7.5 months), 71% of survivors had neurological deficits; 55% had clinically significant disability. Outcome based on PSOM and KOSCHI scores was worse in patients with ICH volume >2% of TBV (p=0.023) and altered mental status at presentation (p = 0.005).
Conclusions
Spontaneous childhood ICH was due mostly to vascular malformations. Acute surgical intervention was commonly performed. Although death was rare, 71% of survivors had persisting neurological deficits. Larger ICH volume and altered mental status predicted clinically significant disability.
doi:10.1161/STROKEAHA.109.568071
PMCID: PMC2821039  PMID: 20019325
intracerebral hemorrhage; outcome; childhood; vascular malformation
12.  Citicoline in Addictive Disorders: A Review of the Literature 
Background
Citicoline is a dietary supplement that has been used as a neuroprotective agent for neurological disorders such as stroke and dementia. Citicoline influences acetylcholine, dopamine, and glutamate neurotransmitter systems; serves as an intermediate in phospholipid metabolism; and enhances the integrity of neuronal membranes. Interest has grown in citicoline as a treatment for addiction since it may have beneficial effects on craving, withdrawal symptoms, and cognitive functioning, as well as the ability to attenuate the neurotoxic effects of drugs of abuse.
Objectives
To review the literature on citicoline’s use in addictive disorders.
Methods
Using PubMed we conducted a narrative review of the clinical literature on citicoline related to addictive disorders from the years 1900 to 2013 using the following keywords: citicoline, CDP-choline, addiction, cocaine, alcohol, substance abuse, and substance dependence. Out of approximately 900 first hits, nine clinical studies have been included in this review.
Results
Most addiction research investigated citicoline for cocaine use. The findings suggest that it is safe and well tolerated. Furthermore, citicoline appears to decrease craving and is associated with a reduction in cocaine use, at least at high doses in patients with both bipolar disorder and cocaine dependence. Limited data suggest citicoline may also hold promise for alcohol and cannabis dependence and in reducing food consumption.
Conclusions
Currently, there is limited research on the efficacy of citicoline for addictive disorders, but the available literature suggests promising results. Future research should employ larger sample sizes, increased dosing, and more complex study designs.
doi:10.3109/00952990.2014.925467
PMCID: PMC4139283  PMID: 24950234
Citicoline; Addiction; Substance Use; Substance Abuse; Bipolar Disorder; Cocaine; Substance Dependence; Alcohol; Methamphetamine
13.  The Association between Specific Substances of Abuse and Subcortical Intracerebral Hemorrhage Versus Ischemic Lacunar Infarction 
Background: Hypertension damages small vessels, resulting in both lacunar infarction and subcortical intracerebral hemorrhage (ICH). Substance abuse has also been linked to small vessel pathology. This study explores whether the use of specific substances (e.g., cocaine, tobacco) is associated with subcortical ICH over ischemia in hypertensive individuals.
Methods: Patients with hypertension, admitted with lacunar infarcts (measuring <2.0 cm) or subcortical ICH, were included in analysis. Brain MRIs and head CTs were retrospectively reviewed along with medical records. Demographic information and history of substance use (illicit/controlled: cocaine, heroin, marijuana, benzodiazepines, and methadone; alcohol; and tobacco) was obtained. “Current use” and “history of use” were determined from patient history or a positive toxicology screen. “Heavy use” was defined as: smoking- ≥0.5 packs per day or 10 pack-years; alcohol- average of >1 drink per day (women), >2 drinks per day (men). Logistic regression was performed with ICH as the dependent variable comparing those presenting with ICH to those presenting with ischemia.
Results: Of the 580 patients included in analysis, 217 (37%) presented with ICH. The average age was similar between the two groups (64.7 versus 66.3 years). Illicit/controlled drug use was associated with a significantly increased risk of ICH over stroke in unadjusted models (25 versus 15%, p = 0.02), with the largest effect seen in users ≥65 years old (not statistically significant). Smoking was associated with ischemia over ICH in a dose-dependent manner: any history of smoking OR 1.84, CI 1.19–2.84; current use OR 2.23, CI 1.37–3.62; heavy use OR 2.48, CI 1.50–4.13. Alcohol use was not preferentially associated with either outcome (p = 0.29).
Conclusion: In hypertensive patients, tobacco use is associated with an increased risk of subcortical ischemia compared to ICH, while use of illicit/controlled substances appears to be predictive of hemorrhage.
doi:10.3389/fneur.2014.00174
PMCID: PMC4159993  PMID: 25309502
intracerebral hemorrhage; stroke; hypertension; tobacco; alcohol; drug abuse
14.  Intravenous tPA Therapy Does Not Worsen Acute Intracerebral Hemorrhage in Mice 
PLoS ONE  2013;8(2):e54203.
Tissue plasminogen activator (tPA) is the only FDA-approved treatment for reperfusing ischemic strokes. But widespread use of tPA is still limited by fears of inadvertently administering tPA in patients with intracerebral hemorrhage (ICH). Surprisingly, however, the assumption that tPA will worsen ICH has never been biologically tested. Here, we assessed the effects of tPA in two models of ICH. In a mouse model of collagenase-induced ICH, hemorrhage volumes and neurological deficits after 24 hrs were similar in saline controls and tPA-treated mice, whereas heparin-treated mice had 3-fold larger hematomas. In a model of laser-induced vessel rupture, tPA also did not worsen hemorrhage volumes, while heparin did. tPA is known to worsen neurovascular injury by amplifying matrix metalloproteinases during cerebral ischemia. In contrast, tPA did not upregulate matrix metalloproteinases in our mouse ICH models. In summary, our experimental data do not support the assumption that intravenous tPA has a deleterious effect in acute ICH. However, due to potential species differences and the inability of models to fully capture the dynamics of human ICH, caution is warranted when considering the implications of these findings for human therapy.
doi:10.1371/journal.pone.0054203
PMCID: PMC3568130  PMID: 23408937
15.  Ischemic-appearing electrocardiographic changes predict myocardial injury in patients with intracerebral hemorrhage☆☆☆★ 
Objectives
Myocardial injury is common among patients with intracerebral hemorrhage (ICH). However, it is challenging for emergency physicians to recognize acute myocardial injury in this population, as electrocardiographic (ECG) abnormalities are common in this setting. Our objective is to examine whether ischemic-appearing ECG changes predict subsequent myocardial injury in the context of ICH.
Methods
Consecutive patients with primary ICH presenting to a single academic center were prospectively enrolled. Electrocardiograms were retrospectively reviewed by 3 independent readers. Anatomical areas of ischemia were defined as I and aVL; II, III, and aVF; V1 to V4; and V5 and V6. Medical record review identified myocardial injury, defined as troponin I or T elevation (cutoff 1.5 and 0.1 ng/mL, respectively), within 30 days.
Results
Between 1998 and 2004, 218 patients presented directly to our emergency department and did not have a do-not-resuscitate/do-not-intubate order; arrival ECGs and troponin levels were available for 206 patients. Ischemic-appearing changes were noted in 41% of patients, and myocardial injury was noted in 12% of patients. Ischemic-appearing changes were more common in patients with subsequent injury (64% vs 37%; P = .02). After multivariable analysis controlling for age and cardiac risk factors, ischemic-appearing ECG changes independently predicted myocardial injury (odds ratio, 3.2; 95% confidence interval, 1.3-8.2). In an exploratory analysis, ischemic-appearing ECG changes in leads I and aVL as well as V5 and V6 were more specific for myocardial injury (P = .002 and P = .03, respectively).
Conclusion
In conclusion, although a range of ECG abnormalities can occur after ICH, the finding of ischemic-appearing changes in an anatomical distribution can help predict which patients are having true myocardial injury.
doi:10.1016/j.ajem.2011.02.007
PMCID: PMC3684165  PMID: 21450435
16.  Mouse Models of Intracerebral Hemorrhage in Ventricle, Cortex, and Hippocampus by Injections of Autologous Blood or Collagenase 
PLoS ONE  2014;9(5):e97423.
Intracerebral hemorrhage (ICH) is a devastating condition. Existing preclinical ICH models focus largely on striatum but neglect other brain areas such as ventricle, cortex, and hippocampus. Clinically, however, hemorrhagic strokes do occur in these other brain regions. In this study, we established mouse hemorrhagic models that utilize stereotactic injections of autologous whole blood or collagenase to produce ventricular, cortical, and hippocampal injury. We validated and characterized these models by histology, immunohistochemistry, and neurobehavioral tests. In the intraventricular hemorrhage (IVH) model, C57BL/6 mice that received unilateral ventricular injections of whole blood demonstrated bilateral ventricular hematomas, ventricular enlargement, and brain edema in the ipsilateral cortex and basal ganglia at 72 h. Unilateral injections of collagenase (150 U/ml) caused reproducible hematomas and brain edema in the frontal cortex in the cortical ICH (c-ICH) model and in the hippocampus in the hippocampal ICH (h-ICH) model. Immunostaining revealed cellular inflammation and neuronal death in the periventricular regions in the IVH brain and in the perihematomal regions in the c-ICH and h-ICH brains. Locomotor abnormalities measured with a 24-point scoring system were present in all three models, especially on days 1, 3, and 7 post-ICH. Locomotor deficits measured by the wire-hanging test were present in models of IVH and c-ICH, but not h-ICH. Interestingly, mice in the c-ICH model demonstrated emotional abnormality, as measured by the tail suspension test and forced swim test, whereas h-ICH mice exhibited memory abnormality, as measured by the novel object recognition test. All three ICH models generated reproducible brain damage, brain edema, inflammation, and consistent locomotor deficits. Additionally, the c-ICH model produced emotional deficits and the h-ICH model produced cognitive deficits. These three models closely mimic human ICH and should be useful for investigating the pathophysiology of ICH in ventricle, cortex, and hippocampus and for evaluating potential therapeutic strategies.
doi:10.1371/journal.pone.0097423
PMCID: PMC4022524  PMID: 24831292
17.  Activation of c-Jun N-terminal kinase in a rat model of intracerebral hemorrhage: the role of iron 
Neuroscience research  2008;63(2):100-105.
Iron accumulates in the brain and contributes to brain injury after intracerebral hemorrhage (ICH). The c-Jun-N-terminal kinase (JNK) signaling pathway mediates cell death after ischemic stroke, however, the involvement of JNK in ICH is not well known. This study investigated whether the JNK signaling pathway is activated by iron after ICH. Male Sprague-Dawley rats received an infusion of autologous whole blood (as a model of ICH) or ferrous iron into the right basal ganglia and control rats had an infusion of saline. Some ICH rats were treated with either deferoxamine (DFX), an iron chelator, or vehicle. Activation of JNK was measured by Western blot analysis and immunohistochemistry. Free iron in cerebrospinal fluid (CSF) and behavioral outcomes following ICH were also examined. We found that activated-JNK in the brain were increased after ICH, and an intracerebral infusion of ferrous iron also upregulated brain activated-JNK. Free iron accumulated in CSF and Systemic administration of DFX after ICH reduces free iron contents in CSF, suppresses JNK activation and improves ICH-induced neurological deficits. Our results demonstrated that the JNK signaling pathway is activated after ICH and iron may contribute to this activation. DFX reduces free iron levels and attenuates activation of JNK suggesting iron chelation may be useful therapy for ICH patients.
doi:10.1016/j.neures.2008.10.013
PMCID: PMC2649665  PMID: 19100788
cerebral hemorrhage; c-Jun-N-terminal kinase; deferoxamine; iron
18.  Treatment of 817 patients with spontaneous supratentorial intracerebral hemorrhage: characteristics, predictive factors and outcome 
Clinics and Practice  2012;2(3):e56.
The aim of this study was to present the data of a large cohort of patients with spontaneous supratentorial intracerebral hemorrhage (ICH), who were treated in our department and give a current overview considering special clinical characteristics, performed therapy and different predictive factors for morbidity and mortality. We reviewed the data of all patients with spontaneous ICH, who were treated in our department in a time span of 11 years through an analysis of our prospective database. Patients with spontaneous supratentorial ICH were included in the study. Patients with hemorrhage associated to vascular malformation or to cerebral ischemic stroke were excluded. The clinical performance at time of admission and discharge were scored using the Glasgow coma scale (GCS) and the Glasgow outcome scale (GOS) respectively. The patients' cohort was divided into surgically and conservatively treated groups. Statistical analysis [Analysis of Variance (ANOVA) and χ2-test] was done for various parameters to analyze their impact on morbidity and mortality. In total, we analyzed the data of 817 patients (364 female and 453 male). Two hundred and sixty-nine patients (32%) were treated conservatively and 556 patients (68%) underwent surgical procedures, i.e. cerebrospinal fluid drainage in 110 (19.8%), craniotomy in 338 (60.7%) and application of both methods in 108 patients (19.4%). Total mortality rate was estimated with 23.5%. GCS<8, age over 70 years, intraventricular and basal ganglia hemorrhage, coumadin medication, combination of co-morbidities, hypertensive hemorrhage and postoperative re-bleeding were statistically significant risk factors for worse outcome (GOS 1 and 2) in the operated group. Similar to the observations of the operated group, GCS<8, age over 70 years and coumadin medication were statistically significant for worse outcome in the conservative group. In contrast, lobar plus basal ganglia ICH and multi-lobar hemorrhages were the most significant factors for worse outcome in the conservative group. The results of our study show that ICH remains a multifarious disease and challenges neurosurgeons repeatedly. Selection of the treatment modality and prediction for neurofunc-tional outcome underlies various parameters. Treatment recommendations of ICH remain an unsolved issue. The consideration of the GCS grade at admission is the most important predictive factor. Old age is not an absolute contraindication for surgery, but cumulative multi-morbidity, especially cerebrovascular and cardiovascular diseases and oral anticoagulant therapy should be regarded critically in view of surgical treatment.
doi:10.4081/cp.2012.e56
PMCID: PMC3981302  PMID: 24765455
intracerebral hemorrhage; supratentorial intracerebral hemorrhage; spontaneous hemorrhage; predictive factors; outcome.
19.  Factors associated with in-hospital mortality following intracerebral hemorrhage: a three-year study in Tehran, Iran 
BMC Neurology  2004;4:9.
Background
Primary intracerebral hemorrhage (ICH) is one of the common vascular insults with a relatively high rate of mortality. The aim of the current study was to determine the mortality rate and to evaluate the influence of various factors on the mortality of patients with intracerebral hemorrhage (ICH). Demographic characteristics along with clinical features and neuroimaging information on 122 patients with primary ICH admitted to Sina Hospital between 1999–2002 were assessed by multivariate analysis.
Results
Of 122 patients diagnosed with intracerebral hemorrhage, 70 were men and 52 were women. Sixtynine percent of subjects were between 60 to 80 years of age. A history of hypertension was the primary cause in 67.2% of participants and it was found more frequent compared to other cardiovascular risk factors such as a history of ischemic heart disease (17.2%), diabetes mellitus (18%) and cigarette smoking (13.1%).
The overall mortality rate among ICH patients admitted to the hospital was 46.7%. About one third of the deaths occurred within the first two days after brain injury. Factor independently associated with in-hospital mortality were Glasgow Coma Scale (GCS) score (≤ 8), diabetes mellitus disease, volume of hematoma and and intraventricular hematoma.
Conclusion
Higher rate of mortality were observed during the first two weeks of hospitalization following ICH. Neuroimaging features along with GCS score can help the clinicians in developing their prognosis.
doi:10.1186/1471-2377-4-9
PMCID: PMC449712  PMID: 15193159
Intracerebral hemorrhage; stroke; GCS; outcome
20.  Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) II: Design, Methods, and Rationale 
Neurocritical Care  2011;15(3):559-576.
The December 2003 report from the National Institute of Neurological Disorders and Stroke (NINDS) Workshop on priorities for clinical research in intracerebral hemorrhage (ICH) recommended clinical trials for evaluation of blood pressure management in acute ICH as a leading priority. The Special Writing Group of the Stroke Council of the American Heart Association in 1999 and 2007 emphasized the need for clinical trials to ensure evidence-based treatment of acute hypertensive response in ICH. To address important gaps in knowledge, we conducted a pilot study funded by the NINDS, Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) I Trial, during 2004–2008 to determine the appropriate level of systolic blood pressure (SBP) reduction. We now have initiated a multicenter, randomized Phase III trial, the ATACH II Trial, to definitively determine the efficacy of early, intensive, anti-hypertensive treatment using intravenous (IV) nicardipine initiated within 3 h of onset of ICH and continued for the next 24 h in subjects with spontaneous supratentorial ICH. The primary hypothesis of this large (N = 1,280), streamlined, and focused trial is that SBP reduction to ≤140 mm Hg reduces the likelihood of death or disability at 3 months after ICH, defined by modified Rankin scale score of 4–6, by at least 10% absolute compared to standard SBP reduction to ≤180 mm Hg. The ATACH II trial is a natural extension of numerous case series, the subsequent ATACH I pilot trial, and a preliminary, randomized, and controlled trial in this patient population funded by the Australian National Health and Medical Research Council. Both trials recently confirmed the safety and tolerability of both the regimen and goals of antihypertensive treatment in acutely hypertensive patients with ICH, as proposed in the present trial. The underlying mechanism for this expected beneficial effect of intensive treatment is presumably mediated through reduction of the rate and magnitude of hematoma expansion observed in approximately 73% of the patients with acute ICH. The Australian trial provided preliminary evidence of attenuation of hematoma expansion with intensive SBP reduction. The ATACH II trial will have important public health implications by providing evidence of, or lack thereof, regarding the efficacy and safety of acute antihypertensive treatment in subjects with ICH. This treatment represents a strategy that can be made widely available without the need for specialized equipment and personnel, and therefore, can make a major impact upon clinical practice for treating patients with ICH.
doi:10.1007/s12028-011-9538-3
PMCID: PMC3340125  PMID: 21626077
Intracerebral hemorrhage; Clinical trial; Randomization; Acute hypertensive response; Hematoma enlargement
21.  Challenges and controversies in the medical management of primary and antithrombotic-related intracerebral hemorrhage 
Intracerebral hemorrhage (ICH) represents 10–15% of all cerebrovascular events, and is associated with substantial morbidity and mortality. In contrast to ischemic cerebrovascular disease in which acute therapies have proven beneficial, ICH remains a more elusive condition to treat, and no surgical procedure has proven to be beneficial. Aspects pertinent to medical ICH management include cessation or minimization of hematoma enlargement, prevention of intraventricular extension, and treatment of edema and mass effect. Therapies focusing on these aspects include prothrombotic (hemostatic) agents, antihypertensive strategies, and antiedema therapies. Therapies directed towards the reversal of antithrombosis caused by antiplatelet and anticoagulant agents are frequently based on limited data, allowing for diverse opinions and practice styles. Several newer anticoagulants that act by direct thrombin or factor Xa inhibition have no natural antidote, and are being increasingly used for various prophylactic and therapeutic indications. As such, these new anticoagulants will inevitably pose major challenges in the treatment of patients with ICH. Ongoing issues in the management of patients with ICH include the need for effective treatments that not only limit hematoma expansion but also result in improved clinical outcomes, the identification of patients at greatest risk for continued hemorrhage who may most benefit from treatment, and the initiation of therapies during the hyperacute period of most active hemorrhage. Defining hematoma volume increases at various anatomical locations that translate into clinically meaningful outcomes will also aid in directing future trials for this disease. The focus of this review is to underline and discuss the various controversies and challenges involved in the medical management of patients with primary and antithrombotic-related ICH.
doi:10.1177/1756285611422267
PMCID: PMC3251899  PMID: 22276075
antithrombotic; challenges; controversies; hematoma expansion; intracerebral hemorrhage; medical management; primary; review
22.  CURCUMIN ATTENUATES HEMATOMA SIZE AND NEUROLOGICAL INJURY FOLLOWING INTRACEREBRAL HEMORRHAGE IN MICE 
Journal of neurosurgery  2011;115(1):116-123.
Objective
Intracerebral hemorrhage (ICH) is associated with significant patient morbidity and mortality. Acute hematoma enlargement is an important predictor of neurological injury and poor clinical prognosis; however, neurosurgical clot evacuation may not be feasible in all patients and treatment options remain largely supportive. Thus, novel therapeutic approaches to promote hematoma resolution are needed. In the present study, we investigated whether the curry spice, curcumin, limited neurovascular injury following ICH in mice.
Methods
ICH was induced in adult male CD-1 mice by the intracerebral administration of collagenase or autologous blood. Clinically-relevant doses of curcumin (75–300 mg/kg) were administered up to 6 hours after ICH and hematoma volume, inflammatory gene expression, blood-brain barrier permeability, and brain edema were assessed over the first 72 hours. Neurological assessments were performed to correlate neurovascular protection with functional outcomes.
Results
Curcumin increased hematoma resolution at 72 hours post-ICH. This effect was associated with a significant reduction in the expression of the pro-inflammatory mediators, tumor necrosis factor-α, interleukin-6, and interleukin-1β. Curcumin also reduced disruption of the blood-brain barrier and attenuated the formation of vasogenic edema following ICH. Consistent with the reduction in neuroinflammation and neurovascular injury, curcumin significantly improved neurological outcome scores after ICH.
Conclusion
Curcumin promoted hematoma resolution and limited neurological injury following ICH. These data may indicate clinical utility for curcumin as an adjunct therapy to reduce brain injury and improve patient outcome.
doi:10.3171/2011.2.JNS10784
PMCID: PMC3153730  PMID: 21417704
Hemorrhagic stroke; vasogenic edema; blood-brain barrier; hematoma
23.  PREDICTORS OF HIGHLY PREVALENT BRAIN ISCHEMIA IN INTRACEREBRAL HEMORRHAGE 
Annals of Neurology  2012;71(2):199-205.
Objective
To determine the prevalence, characteristics, risk factors and temporal profile of concurrent ischemic lesions in patients with acute primary intracerebral hemorrhage (ICH).
Methods
Patients were recruited within a prospective, longitudinal, magnetic resonance imaging (MRI) based study of primary ICH. Clinical, demographic, and MRI data were collected on all subjects at baseline and 1 month.
Results
Of the 138 patients enrolled, mean age was 59 years, 54% were male, 73% black, and 84% had a history of hypertension. At baseline, ischemic lesions on diffusion-weighted imaging (DWI) were found in 35% of patients. At 1 month, lesions were present in 27%, and of these lesions, 83% were new and not present at baseline. ICH volume (p=0.025), intraventricular hemorrhage (p=0.019), presence of microbleeds (p=0.024), and large, early reductions in mean arterial pressure (p=0.003) were independent predictors of baseline DWI lesions. A multivariate logistical model predicting the presence of 1 month DWI lesions included history of any prior stroke (p=0.012), presence of 1 or more microbleeds (p=0.04), black race (p=0.641), and presence of a DWI lesion at baseline (p=0.007)
Interpretation
This study demonstrates that more than 1/3 of patients with primary ICH have active cerebral ischemia at baseline remote from the index hematoma, and 1/4 of patients experience ongoing, acute ischemic events at 1 month. Multivariate analyses implicate blood pressure reductions in the setting of an active vasculopathy as a potential underlying mechanism. Further studies are needed to determine the impact of these lesions on outcome and optimal management strategies to arrest vascular damage.
doi:10.1002/ana.22668
PMCID: PMC3298034  PMID: 22367992
24.  Eight weeks of citicoline treatment does not perturb sleep/wake cycles in cocaine-dependent adults 
Background
Citicoline (cytidine-5’-diphosphate) is a mononucleotide composed of ribose, cytosine, pyrophosphate, and choline, and is involved in the biosynthesis of the structural phosopholipids of cell membranes. Treatment with citicoline, improves memory in patients with dementia, and reduces damage to the brain after traumatic brain injury or stroke. Recent research has been conducted to assess whether citicoline is an effective treatment for cocaine dependence. In cocaine-dependent individuals, withdrawal from cocaine is associated with disturbed sleep, which may contribute to the high rate of relapse to cocaine use. Therefore, it is important to know the impact of citicoline on the sleep/wake cycle in these individuals in order to rate its overall efficacy.
Method
In this double-blind, placebo-controlled trial, the effects of citicoline treatment on the sleep/wake cycles of cocaine dependent participants were assessed. The results of the current study are reported as part of a larger study, consisting of an eight-week treatment period to assess the efficacy of longer-term treatment with citicoline at decreasing cocaine consumption in cocaine-dependent polydrug using participants.
Results
In this non-abstinent, cocaine-dependent population, citicoline had no effect on any of the sleep parameters measured including sleep efficiency, sleep latency, total sleep time, number of waking episodes, time awake per episode, amount of time in bed spent moving, number of sleep episodes, time asleep per episode, and amount of time in bed spent immobile.
Conclusions
These data suggest that eight weeks of citicoline administration does not disturb sleep/wake cycles of cocaine-dependent individuals.
doi:10.1016/j.pbb.2011.03.003
PMCID: PMC3081995  PMID: 21397626
citicoline; CDP-choline; sleep; cocaine
25.  Targeting heme oxygenase after intracerebral hemorrhage 
Intracerebral hemorrhage (ICH) is the primary event in approximately 10% of strokes, and has higher rates of morbidity and mortality than ischemic stroke. Experimental evidence suggests that the toxicity of hemoglobin and its degradation products contributes to secondary injury that may be amenable to therapeutic intervention. Hemin, the oxidized form of heme, accumulates in intracranial hematomas to cytotoxic levels. The rate limiting step of its breakdown is catalyzed by the heme oxygenase (HO) enzymes, which consist of inducible HO-1 and constitutively-expressed HO-2. The effect of these enzymes on perihematomal injury and neurological outcome has been investigated in ICH models using both genetic and pharmacological approaches to alter their expression, with variable results reported. These findings are summarized and reconciled in this review; therapeutic strategies that may optimize HO expression and activity after ICH are described.
doi:10.14800/ttnd.474
PMCID: PMC4310000  PMID: 25642455
intracerebral hemorrhage; iron; oxidative stress; stroke; subarachnoid hemorrhage

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