Sivenius J, Sarasoja T, Aaltonen H,
Heinonen E, Kilkku O, Reinikainen K.

Department of Neuroscience and Neurology
University of Kuopio, Finland.
juhani.sivenius@fimnet.fi
Neurorehabil Neural Repair 2001;15(3):183-90

Abstract

OBJECTIVE: Selegiline (deprenyl) is a selective monoamine oxidase B (MAO-B) inhibitor used in the treatment of Parkinson’s disease. In addition, it is thought to rescue neurons with a loss of target-derived trophic support. Several mechanisms have been proposed to explain these phenomena, such as the production of neurotrophic actions through astrocyte activation, reduction of free radical production, or the presence of antiapoptotic properties. The aim of this study was to investigate whether the systemic administration of selegiline (deprenyl) facilitates recovery after a cerebral infarction in humans.

METHODS: This phase II study was randomized, double-blind, and placebo controlled. Selegiline (deprenyl), 5 mg, or matched placebo was given twice a day for 3 months. The drug therapy was started within 48 h after a hemispheric infarction in the territory of middle cerebral artery. There were 24 patients recruited. Twenty patients were followed up to 3 months or until their death, and they represent the efficacy analysis group. The primary efficacy parameters were Scandinavian Stroke Scale (SSS), Barthel Index (BI), and Fugl-Meyer Scale (FMS). Secondary parameters were Zung Self-Rating Depression Scale (ZDS) and 15-Dimensional Measure of Health Related Quality of Life test (15-D).

RESULTS: SSS improved statistically significantly from the baseline when compared with placebo (p = 0.019). The results were parallel among the other two primary efficacy variables (BI and FMS), showing a positive trend for selegiline (deprenyl), although they did not reach statistical significance. Similarly, in the analysis of the secondary efficacy variables, both the 15-D test and ZDS supported this positive trend in favor of selegiline (deprenyl), although no statistically significant differences between groups were found (p = 0.06 in 15-D test).

CONCLUSIONS: Selegiline (deprenyl) seems to be beneficial after a cerebral infarction. This benefit may be due to the enhancement of the recovery process.

Feigin VL, Doronin BM, Popova TF, Gribatcheva EV, Tchervov DV.

Department of Epidemiology and Preventive Medicine,
Institute of Internal Medicine,
Siberian Branch of the Russian Academy of Medical Science, Novosibirsk, Russia. v.feigin@ctru.auckland.ac.nz
Eur J Neurol 2001 Jan;8(1):81-5

Abstract

The aim of the study was to assess the safety and feasibility of a clinical trial on the effect of vinpocetine, a synthetic ethyl ester of apovincamine, in acute ischaemic stroke. Thirty consecutive patients with computed tomography verified diagnosis of acute ischaemic stroke, who could receive drug treatment within 72 h of stroke onset, were enrolled. The patients were randomly allocated to receive either low-molecular weight dextran alone or in combination with vinpocetine. Poor outcome was defined as being dead or having a Barthel index of < 70 or a Rankin score of 3–5. Intention-to-treat analysis was applied. One-tenth of all hospitalized patients with acute ischaemic stroke were eligible for the trial. Thirty eligible patients were treated with either low-molecular weight dextran alone (mean age 57.9 11.6 years, n = 15) or in combination with vinpocetine (mean age 60.8 6.6 years, n = 15). The two treatment groups were comparable with respect to major prognostic variables. A relative risk (RR) reduction of poor outcome at 3 months follow-up was 30% (RR = 0.7; 95% confidence interval [CI] 0.1–3.4), as defined by the modified Barthel Index, and 60% as defined by the modified Ranking score (RR = 0.4, 95% CI: 0.1–1.7). The National Institute of Health (NIH–NINDS) Stroke Scale score was marginally significantly better in the vinpocetine treated group at 3 months of follow-up (P = 0.05, ANOVA). No significant adverse effects were seen. This pilot study shows that a full-scale randomized double-blind, placebo-controlled trial of vinpocetine treatment in acute ischaemic stroke is feasible and warranted.

Bonoczk P, Panczel G, Nagy Z.

Chemical Works of Gedeon Richter Ltd.
Budapest, Hungary
Eur J Ultrasound 2002 Jun;15(1-2):85-91

Abstract

OBJECTIVE: To investigate the effect of vinpocetine on cerebral blood flow (CBF) in the compromised circulation of a stroke affected hemisphere using transcranial Doppler (TCD) and near infrared spectroscopy (NIRS) methods.

METHODS: 43 patients with ischemic stroke were randomized into vinpocetine and placebo group in a double blind, placebo-controlled study of the effect of a single-dose i.v. infusion of vinpocetine on cerebral blood perfusion and oxygenation. In the vinpocetine group 20 mg vinpocetine in 500 ml saline, in the placebo group 500 ml saline alone were administered. The concentrations of oxy-, reduced- and total hemoglobin were measured by NIRS frontolaterally on the side of lesion while the mean cerebral blood flow velocity (CBFV), the pulsatility index (PI) and Doppler spectral intensity (DSI) were monitored by TCD in the middle cerebral artery on the same side. Values were averaged for the first 5 min prior to the infusion and for the last 5 min of infusion and they were compared between groups.

RESULTS: The concentration of all three chromophores increased during infusion in the vinpocetine group (mean dHbT = 1.03, CI(95) = 0.84, P = 0.058; mean dHbO = 0.92, CI(95) = 0.91, P = 0.071; mean dHb = 0.10, CI(95) = 0.21, P = 0.297). The HbT and HbO showed a substantially smaller increase in the placebo group (mean dHbT = 0.31, CI(95) = 0.74, P = 0.22; mean dHbO = 0.57, CI(95) = 0.80, P = 0.094) while the Hb decreased (mean dHb = -0.26, CI(95) = 0.29, P = 0.05). Comparing to the placebo group Hb increased significantly in the vinpocetine group (P = 0.027) while the increase of HbO and HbT did not reach the level of significance (P = 0.29 and 0.11). DSI showed a significantly larger increase in the vinpocetine than in placebo group (dDSI=25.8 CI(95)=8.8 [vinpocetine ]; dDSI =3.3, CI(95) = 3.7 [Placebo], P < 0.005). The CBFV and PI did not differ significantly between groups. (dVm = 5.02.98 cm/s [vinpocetine], dVm = 4.12.57 cm/s [Placebo], P = 0.28; dPI = 0.08 [vinpocetine], dPI = 0.09 [Placebo]; P = 0.47).

CONCLUSION: vinpocetine increases cerebral perfusion and parenchymal oxygen extraction as well. The increased perfusion was indicated by NIRS and by TCD measurement of DSI while conventional velocity and pulsatility measurements failed to detect theses effects. NIRS is a sensitive, feasible method of measuring changes in regional blood flow and tissue oxygenation in the superficial cortex.

Bonoczk P, Gulyas B, Adam-Vizi V, Nemes A, Karpati E,
Kiss B, Kapas M, Szantay C, Koncz I, Zelles T, Vas A.

Chemical Works of Gedeon Richter Ltd.,
Budapest, Hungary
Brain Res Bull 2000 Oct;53(3):245-54

Abstract

Vinpocetine (ethyl apovincaminate) discovered during the late 1960s has successfully been used in the treatment of central nervous system disorders of cerebrovascular origin for decades. The increase in the regional cerebral blood flow in response to vinpocetine administration is well established and strengthened by new diagnostical techniques (transcranial Doppler, near infrared spectroscopy, positron emission tomography). The latest in vitro studies have revealed the effect of the compound on Ca(2+)/calmodulin dependent cyclic guanosine monophosphate-phosphodiesterase 1, voltage-operated Ca(2+) channels, glutamate receptors and voltage dependent Na(+)-channels; the latest being especially relevant to the neuroprotective action of vinpocetine. The good brain penetration profile and heterogenous brain distribution pattern (mainly in the thalamus, basal ganglia and visual cortex) of labelled vinpocetine were demonstrated by positron emission tomography in primates and man. Multicentric, randomized, placebo-controlled clinical studies proved the efficacy of orally administered vinpocetine in patients with organic psychosyndrome. Recently positron emission tomography studies have proved that vinpocetine is able to redistribute regional cerebral blood flow and enhance glucose supply of brain tissue in ischemic post-stroke patients.

Szakall S, Boros I, Balkay L, Emri M, Fekete I, Kerenyi L, Lehel S,
Marian T, Molnar T, Varga J, Galuska L, Tron L, Bereczki D, Csiba L, Gulyas B.

PET Centre,
Debrecen University Medical School, Hungary.
J Neuroimaging 1998 Oct;8(4):197-204

Abstract

The effects of vinpocetine on the cerebral glucose metabolism of chronic stroke patients are studied with positron emission tomography. The regional and global cerebral metabolic rates of glucose (CMRglu) and the kinetic constants related to them are quantified before and after single-dose intravenous vinpocetine treatment. These measurements are completed with transcranial Doppler sonography and single photon emission computed tomography to explore the possible mechanisms underlying the resulting changes in glucose uptake and metabolism in the brain. The authors’ findings indicate that a single-dose vinpocetine treatment, although it does not affect significantly the regional or global metabolic rates of glucose, improves significantly the transport of glucose (both uptake and release) through the blood-brain barrier in the whole brain, the entire contralateral hemisphere, and in the brain tissue around the infarct area of the symptomatic hemisphere. These changes are in accord with increased blood flow in the entire contralateral hemisphere as well as decreased blood flow velocity and increased peripheral vessel resistance in the entire symptomatic hemisphere.

Hayakawa M

Department of Geriatrics,
Nagoya University School of Medicine, Japan.
Arzneimittelforschung 1992 Apr;42(4):425-7

Abstract

Reduction in red blood cell deformability is a contributory factor in stroke disease, and it has been postulated that red blood cell rigidification may be improved by drug treatment. In this paper the effect of vinpocetine on the deformability of red blood cells from patients with chronic ischemic cerebrovascular disease has been examined. During the administration of vinpocetine for 3 months a significant improvement in red blood cell deformability was observed without adverse effect.

Warach S, Pettigrew LC, Dashe JF, Pullicino P, Lefkowitz DM,
Sabounjian L, Harnett K, Schwiderski U, Gammans R.

National Institute of Neurological Disorders and Stroke,
National Institutes of Health,
Bethesda, MD 20892-4129.
Ann Neurol 2000 Nov;48(5):713-22

Abstract

We examined the effect of the neuroprotective and neurorepairative agent CDP-choline on the growth of cerebral ischemic lesions in a double-blind placebo-controlled study involving patients with acute ischemic stroke using diffusion-weighted magnetic resonance imaging (DWI). Patients with acute ischemic stroke symptom onset 24 hours or less before the start of treatment, National Institutes of Health Stroke Scale (NIHSS) scores of 5 or higher, and lesions of 1 to 120 cc in cerebral gray matter by DWI were enrolled. DWI, T2-weighted magnetic resonance imaging (MRI), perfusion-weighted MRI, and magnetic resonance angiography were obtained at baseline, week 1, and week 12. CDP-choline coline (500 mg/day) was administered orally for 6 weeks, and patients were followed for 12 weeks. The primary assessment was progression of ischemic lesion volume from baseline to 12 weeks as measured by MRI. A total of 100 patients entered the study. The primary MRI analysis included 40 placebo-treated patients and 41 CDP-choline-treated patients with both baseline and week 12 MRI data and failed to demonstrate a significant difference in lesion volume change from baseline to week 12. From baseline to week 12, ischemic lesion volume [all values mean (SE)] expanded by 180% (107) among placebo-treated patients compared with 34% (19) among CDP-choline-treated patients. In a secondary analysis, lesion volume decreased from week 1 to week 12 by 6.9 cc (2.8) on placebo versus 17.2 cc (2.6) on CDP-choline. Baseline variables that were predictors of change in lesion size over 12 weeks were the volume of hypoperfusion (strongest association), baseline NIHSS score, lesion volume on DWI, arterial lesion by magnetic resonance angiography, and categorized elapsed time (< or =12 or >12 hours) from stroke onset to first dose. A marked association between lesion volume reduction and improvement of NIHSS score by seven or more points was observed. Significant correlations between lesion volumes and clinical measures were found, replicating values reported in the literature for smaller case series. We observed a reduction in lesion volume growth from baseline to week 12 with CDP-choline treatment, with a significantly greater reduction in volume from week 1 to week 12 with CDP-choline. We found a significant inverse relationship between lesion volume change over 12 weeks as measured by MRI and clinical outcome for ischemic stroke. This relationship supports the role of DWI as a surrogate marker of clinically meaningful lesion progression in stroke clinical trials. The hypothesis that CDP-choline reduces lesion growth and improves clinical outcome will be tested further.

Clark WM, Warach SJ, Pettigrew LC, Gammans RE, Sabounjian LA.

Oregon Stroke Center,
Oregon Health Sciences University,
Portland OR 97201, USA.
Neurology 1997 Sep;49(3):671-8

Abstract

Citicoline (CDP-choline) is a key intermediary in the biosynthesis of phosphatidylcholine, an important component of the neural cell membrane. It has been shown to produce beneficial effects in both animal models and non-US clinical stroke trials. This study comprised a randomized (3 doses of citicoline to 1 placebo), vehicle-controlled, double-blind trial at 21 US centers. Treatment was to be started within 24 hours of stroke onset and was continued orally for 6 weeks. Final outcome assessments were at 12 weeks. Two hundred fifty-nine patients were enrolled, with approximately 65 in each of the four groups. Mean time from stroke onset to treatment was 14.5 hours, and there were no significant differences in baseline characteristics between the four groups except for patient weight. A significant difference between the groups, favoring citicoline treatment, was seen in terms of functional outcome as measured by the Barthel Index and Rankin scale, neurologic evaluation as measured by the National Institutes of Health (NIH) stroke scale, and cognitive function as measured by the Mini Mental Status Examination. When the baseline NIH stroke scale was used as a covariate, both the 500-mg citicoline group and the 2,000-mg citicoline group had a significant improvement in terms of the percent of patients who had a favorable outcome on the Barthel Index at 90 days. There were no drug-related serious adverse events or deaths in this study. This study suggests that oral citicoline can be used safely with minimal side effects in acute stroke treatment. Citicoline (CDP-choline) appears to improve functional outcome and reduce neurologic deficit with 500 mg of citicoline appearing to be the optimal dose.

Adibhatla RM, Hatcher JF, Dempsey RJ.

Dept of Neurological Surgery and Cardiovascular Research Center
University of Wisconsin, Madison, Wisconsin 53792-3232. adibhatl@neurosurg.wisc.edu
J Neurochem 2002 Jan;80(1):12-23

Abstract

Cytidine-5′-diphosphocholine (citicoline or CDP-choline), an intermediate in the biosynthesis of phosphatidylcholine (PtdCho), has shown beneficial effects in a number of CNS injury models and pathological conditions of the brain. Citicoline improved the outcome in several phase-III clinical trials of stroke, but provided inconclusive results in recent clinical trials. The therapeutic action of citicoline is thought to be caused by stimulation of PtdCho synthesis in the injured brain, although the experimental evidence for this is limited. This review attempts to shed some light on the properties of citicoline that are responsible for its effectiveness. Our studies in transient cerebral ischemia suggest that citicoline might enhance reconstruction (synthesis) of PtdCho and sphingomyelin, but could act by inhibiting the destructive processes (activation of phospholipases). Citicoline neuroprotection may include: (i) preserving cardiolipin (an exclusive inner mitochondrial membrane component) and sphingomyelin; (ii) preserving the arachidonic acid content of PtdCho and phosphatidylethanolamine; (iii) partially restoring PtdCho levels; (iv) stimulating glutathione synthesis and glutathione reductase activity; (v) attenuating lipid peroxidation; and (vi) restoring Na(+)/K(+)-ATPase activity. These observed effects of citicoline could be explained by the attenuation of phospholipase A(2) activation. Based on these findings, a singular unifying mechanism has been hypothesized. Citicoline (CDP-choline) also provides choline for synthesis of neurotransmitter acetylcholine, stimulation of tyrosine hydroxylase activity and dopamine release.

Davalos A, Castillo J, Alvarez-Sabin J, Secades JJ, Mercadal J,
Lopez S, Cobo E, Warach S, Sherman D, Clark WM, Lozano R.

Department of Neurology,
Hospital Universitari Doctor Josep Trueta,
Girona, Spain (A.D.).
Stroke 2002 Dec;33(12):2850-7

Abstract

Background and Purpose- No single neuroprotective agent has been shown to influence outcome after acute stroke. Citicoline (CDP-choline) has been studied worldwide in many clinical trials with positive findings, but only 1 trial has obtained significant results in the primary efficacy variables. Our objective was to evaluate the effects of oral citicoline in patients with acute ischemic stroke by a data pooling analysis of clinical trials. The primary efficacy end point chosen was the common evaluation of recovery, combining National Institutes of Health Stroke Scale /=95 at 3 months using the generalized estimating equations analysis.

METHODS: A systematic search of all prospective, randomized, placebo-controlled, double-blind clinical trials with oral citicoline (Medline, Cochrane, and Ferrer Group bibliographic databases) was undertaken. Individual patient data were extracted from each study and pooled in a single data file. The main inclusion criteria included compatible neuroimaging with ischemic stroke, National Institutes of Health Stroke Scale >/=8, and prior modified Rankin Scale score

RESULTS: Of 1652 randomized patients, 1372 fulfilled the inclusion criteria (583 received placebo, 789 received citicoline). Recovery at 3 months was 25.2% in citicoline-treated patients and 20.2% in placebo-treated patients (odds ratio [OR], 1.33; 95% CI, 1.10 to 1.62; P=0.0034). The dose showing the largest difference with placebo was 2000 mg, with 27.9% of patients achieving recovery (OR, 1.38; 95% CI, 1.10 to 1.72; P=0.0043). The overall safety of citicoline was similar to placebo.

CONCLUSIONS: Treatment with oral citicoline (CDP-choline) within the first 24 hours after onset in patients with moderate to severe stroke increases the probability of complete recovery at 3 months.