Advertisement

Drugs & Aging

, Volume 26, Issue 11, pp 893–915 | Cite as

Cerebrolysin

A Review of its Use in Dementia
  • Greg L. PloskerEmail author
  • Serge Gauthier
Adis Drug Evaluation

Summary

Abstract

Cerebrolysin is a parenterally administered, porcine brain-derived peptide preparation that has pharmacodynamic properties similar to those of endogenous neurotrophic factors. In several randomized, double-blind trials of up to 28 weeks’ duration in patients with Alzheimer’s disease, Cerebrolysin was superior to placebo in improving global outcome measures and cognitive ability. A large, randomized comparison of Cerebrolysin, donepezil or combination therapy showed beneficial effects on global measures and cognition for all three treatment groups compared with baseline. Although not as extensively studied in patients with vascular dementia, Cerebrolysin has also shown beneficial effects on global measures and cognition in this patient population. Cerebrolysin was generally well tolerated in clinical trials, with dizziness (or vertigo) being the most frequently reported adverse event. Although further studies with Cerebrolysin, including longer term trials and further exploration of its use in combination with cholinesterase inhibitors, are needed to more clearly determine its place in the management of Alzheimer’s disease and vascular dementia, available data suggest that Cerebrolysin is a useful addition to the treatment options available for dementia.

Pharmacological Properties

Several in vitro and in vivo studies have shown that Cerebrolysin has neurotrophic effects similar to those of endogenous neurotrophic factors. Cerebrolysin improved the viability of cultured neurons in vitro and rescued medial septal cholinergic neurons following intraperitoneal administration in rats after transections of fimbria-fornix in the brain. Peripheral administration of Cerebrolysin also produced neuroprotective effects, limiting neuronal dysfunction and maintaining the structural integrity of neurons under detrimental conditions in preclinical studies in animal models. In addition, Cerebrolysin showed effects as a synaptic modulator, potentially improving the integrity of neuronal circuits in a transgenic mouse model of Alzheimer’s disease (mThy1-hAPP751), and various in vitro and in vivo studies showed that Cerebrolysin promotes neurogenesis. Behavioural effects, including amelioration of performance deficits in transgenic mice (mThy1-hAPP751), have also been demonstrated with Cerebrolysin. Although its mechanism of action at a molecular level has not been fully elucidated, a potentially significant effect of Cerebrolysin is that of reduced phosphorylation of the amyloid precursor protein and amyloid-β peptide production via modulation of kinases GSK3b and CDK5. Taken together, preclinical and radiolabelling studies indicate that, following peripheral administration, Cerebrolysin crosses the blood-brain barrier in sufficient concentrations to produce pharmacodynamic effects in the CNS.

Therapeutic Efficacy

Several randomized, double-blind, placebo-controlled studies of up to 28 weeks’ duration in patients with Alzheimer’s disease have demonstrated that, compared with placebo, intravenously administered Cerebrolysin produced a consistent, statistically significant improvement on global measures, as assessed by Clinician Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus) or Clinical Global Impression (CGI) of severity or change (CGIS/C). Several of these studies also showed statistically significant improvements on cognition, as assessed by the Alzheimer’s Disease Assessment Scale (ADAS-cog) or its extended version (ADAS-cog-plus). Beneficial effects of Cerebrolysin on these co-primary outcomes were observed in patients with mild to moderate disease as well as in subgroups of patients with greater cognitive impairment at baseline, and when outcomes were measured at the end of the treatment period or several weeks after the final dose. A large, randomized, 28-week comparison of Cerebrolysin, donepezil or combination therapy showed beneficial effects on global measures (CIBIC-plus scores) and cognition (ADAS-cog-plus scores) for all three treatment groups compared with baseline. Although effects on cognitive improvement were most pronounced with combination therapy (−2.339), followed by Cerebrolysin (−1.708) then donepezil (−1.258), there were no statistically significant differences between groups. The proportions of CIBIC responders in the respective treatment groups were 62.7%, 64.1% and 37.8%. Beneficial effects of Cerebrolysin on other outcomes, including behaviour (as assessed by the Neuropsychiatric Inventory), were shown in some trials.

In patients with vascular dementia, Cerebrolysin was superior to placebo, as assessed by CIBIC-plus and ADAS-cog (co-primary endpoints) in a large, well designed, 24-week trial. Other studies with Cerebrolysin in patients with vascular dementia have also demonstrated beneficial effects on global outcomes and cognition.

Tolerability

Tolerability data from studies in patients with dementia indicate that Cerebrolysin was generally well tolerated in all clinical trials. The incidence of any treatment-emergent adverse event was 43.4−64% with Cerebrolysin compared with 38.0−73% with placebo in three larger, placebo-controlled trials in patients with Alzheimer’s disease. Commonly reported adverse events with both Cerebrolysin and placebo included dizziness (or vertigo), headache, increased sweating, nausea, urinary tract infection, depression and fever, although there was marked variability between studies in terms of the type and incidence of adverse events. The incidence of adverse events in the large, active-comparator trial was generally similar between Cerebrolysin, donepezil and combination therapy arms. The most frequently reported adverse events with Cerebrolysin-containing regimens included aggression, agitation, anorexia, arthralgia, delusion, dizziness, headache, hypokinesia, insomnia and urinary tract infection. Donepezil was most frequently associated with diarrhoea, dysthymic disorder, muscle spasms and nausea. In general, adverse events reported with Cerebrolysin in patients with Alzheimer’s disease were broadly similar to those reported in patients with vascular dementia.

Keywords

Dementia Memantine Vascular Dementia Cholinesterase Inhibitor Rivastigmine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Europa Public Health. Alzheimer disease and other dementias [online]. Available from URL: http://ec.europa.eu/health/ph_information/dissemination/diseases/alzheimer_en.htm [Accessed 2009 May 27]
  2. 2.
    National Institute of Neurological Disorders and Stroke. National institutes of Health. Dementia: hope through research [online]. Available from URL: http://www.ninds.nih.gov/disorders/dementias/detail_dementia.htm?css=print [Accessed 2009 May 27]
  3. 3.
    Ferri CP, Prince M, Brayne C, et al. Global prevalence of dementia: a Delphi consensus study. Lancet 2005; 366: 2112–7PubMedCrossRefGoogle Scholar
  4. 4.
    Fumagalli F, Molteni R, Calabrese F, et al. Neurotrophic factors in neurodegenerative disorders: potential for therapy. CNS Drugs 2008; 22(12): 1005–19PubMedCrossRefGoogle Scholar
  5. 5.
    Alzheimer’s Association. 2009 Alheimer’s disease facts and figures [online]. Available from URL: http://www.alz.org/national/documents/report_alzfactsfigures2009.pdf [Accessed 2009 May 27]
  6. 6.
    Robinson DM, Plosker GL. Galantamine extended release. CNS Drugs 2006; 20(8): 673–81PubMedCrossRefGoogle Scholar
  7. 7.
    Scott LJ, Goa KL. Galantamine: a review of its use in Alzheimer’s disease. Drugs 2000; 60(5): 1095–122PubMedCrossRefGoogle Scholar
  8. 8.
    Yang LPH, Keating GM. Rivastigmine transdermal patch: in the treatment of dementia of the Alzheimer’s type. CNS Drugs 2007; 21(11): 957–65PubMedCrossRefGoogle Scholar
  9. 9.
    Spencer CM, Noble S. Rivastigmine: a review of its use in Alzheimer’s disease. Drugs Aging 1998; 13(5): 391–411PubMedCrossRefGoogle Scholar
  10. 10.
    Dooley M, Lamb HM. Donepezil: a review of its use in Alzheimer’s disease. Drugs Aging 2000; 16(3): 199–226PubMedCrossRefGoogle Scholar
  11. 11.
    Goldsmith DR, Scott LJ. Donepezil: in vascular dementia. Drugs Aging 2003; 20(15): 1127–36PubMedCrossRefGoogle Scholar
  12. 12.
    Jönhagen ME. Nerve growth factor treatment in dementia. Alzheimer Dis Assoc Disord 2000; 14Suppl. 1: S31–8PubMedCrossRefGoogle Scholar
  13. 13.
    Cerebrolysin® solution for injection: summary of product characteristics. Unterach, Austria: EBEWE Neuro Pharma GmbH, 2009 MarGoogle Scholar
  14. 14.
    Hartbauer M, Hutter-Paier B, Skofitsch G, et al. Anti-apoptotic effects of the peptidergic drug cerebrolysin on primary cultures of embryonic chick cortical neurons. J Neural Transm 2001; 108(4): 459–73PubMedCrossRefGoogle Scholar
  15. 15.
    Wolf HJ, Hutter-Paier B, Gmeinbauer R, et al. Serum withdrawal induced apoptosis in embryonic chicken cortical neurons in vitro: protection with a neurotrophic pep-tide preparation [abstract no. III-AD-54]. 5th International Conference on Progress in Alzhemier’s and Parkinson’s Disease; 2001 Mar 31–Apr 5; KyotoGoogle Scholar
  16. 16.
    Wronski R, Kronawetter S, Hutter-Paier B, et al. A brain derived peptide preparation reduces the translation dependent loss of a cytoskeletal protein in primary cultured chicken neurons. J Neural Transm Suppl 2000; 59: 263–72PubMedGoogle Scholar
  17. 17.
    Akai F, Hiruma S, Sato T, et al. Neurotrophic factor-like effect of FPF1070 on septal cholinergic neurons after transections of fimbria-fornix in the rat brain. Histol His-topathol 1992 Apr; 7(2): 213–21Google Scholar
  18. 18.
    Alvarez XA, Lombardi VRM, Fernández-Novoa L, et al. Cerebrolysin® reduces microglial activation in vivo and in vitro: a potential mechanism of neuroprotection. J Neural Transm Suppl 2000; 59: 281–92PubMedGoogle Scholar
  19. 19.
    Veinbergs I, Mante M, Mallory M, et al. Neurotrophic effects of Cerebrolysin® in animal models of excitotoxicity. J Neural Transm Suppl 2000; 59: 273–80PubMedGoogle Scholar
  20. 20.
    Ubhi K, Rockenstein E, Doppler E, et al. Neurofibrillary and neurodegenerative pathology in APP-transgenic mice injected with AAV2-mutant TAU: neuroprotective effects of Cerebrolysin. Acta Neuropathol 2009 Jun; 117(6): 699–712PubMedCrossRefGoogle Scholar
  21. 21.
    Rockenstein E, Torrance M, Mante M, et al. Cerebrolysin decreases amyloid-ß production by regulating amyloid protein precursor maturation in a transgenic model of Alzheimer’s disease. J Neurosci Res 2006 May 15; 83(7): 1252–61PubMedCrossRefGoogle Scholar
  22. 22.
    Hartbauer M, Hutter-Paie B, Windisch M. Effects of Cerebrolysin on the outgrowth and protection of processes of cultured brain neurons. J Neural Transm 2001; 108(5): 581–92PubMedCrossRefGoogle Scholar
  23. 23.
    Rockenstein E, Adame A, Mante M, et al. The neuroprotective effects of Cerebrolysin™ in a transgenic model of Alzheimer’s disease are associated with improved behavioral performance. J Neural Transm 2003 Nov; 110(11): 1313–27PubMedCrossRefGoogle Scholar
  24. 24.
    Rockenstein E, Mallory M, Mante M, et al. Effects of Cerebrolysin™ on amyloid-X deposition in a transgenic model of Alzheimer’s disease. J Neural Transm Suppl 2002; 62: 327–36PubMedGoogle Scholar
  25. 25.
    Masliah E, Armasolo F, Veinbergs I, et al. Cerebrolysin ameliorates performance deficits, and neuronal damage in apolipoprotein E-deficient mice. Pharmacol Biochem Behav 1999 Feb; 62(2): 239–45PubMedCrossRefGoogle Scholar
  26. 26.
    Windholz E, Gschanes A, Windisch M, et al. Two peptidergic drugs increase the synaptophysin immunoreactivity in brains of 6-week-old rats. Histochem J 2000 Feb; 32(2): 79–84PubMedCrossRefGoogle Scholar
  27. 27.
    Reinprecht I, Gschanes A, Windisch M, et al. Two peptidergic drugs increase the synaptophysin immunoreactivity in brains of 24-month-old rats. Histochem J 1999 Jun; 31(6): 395–401PubMedCrossRefGoogle Scholar
  28. 28.
    Satou T, Imano M, Akai F, et al. Morphological observation of effects of Cerebrolysin on cultured neural cells. Adv Biosci 1993; 87: 195–6Google Scholar
  29. 29.
    Satou T, Itoh T, Tamai Y, et al. Neurotrophic effects of FPF-1070 (Cerebrolysin®) on cultured neurons from chicken embryo dorsal root ganglia, ciliary ganglia, and sympathetic trunks. J Neural Transm 2000; 107(11): 1253–62PubMedCrossRefGoogle Scholar
  30. 30.
    Satou T, Itoh T, Fujimoto M, et al. Neurotrophic-like effects of FPF-1070 on cultured neurons from chick embryonic dorsal root ganglia [in Japanese]. Jpn Pharmacol Ther 1994; 22(4): 205–12Google Scholar
  31. 31.
    Mallory M, Honer W, Hsu L, et al. In vitro synaptotrophic effects of Cerebrolysin in NT2N cells. Acta Neuropathol 1999 May; 97(5): 437–46PubMedCrossRefGoogle Scholar
  32. 32.
    Ono T, Takahashi M, Nakamura Y, et al. Phase I study of FPF 1070 (Cerebrolysin) ampuls in healthy volunteers: single and multiple dose study [in Japanese]. Jpn Pharmacol Ther 1992; 20(4): 199–215Google Scholar
  33. 33.
    Rockenstein E, Mante M, Adame A, et al. Effects of Cerebrolysin™ on neurogenesis in an APP transgenic model of Alzheimer’s disease. Acta Neuropathol 2007 Mar; 113(3): 265–75PubMedCrossRefGoogle Scholar
  34. 34.
    Tatebayashi Y, Lee MH, Li L, et al. The dentate gyrus neurogenesis: a therapeutic target for Alzheimer’s disease. Acta Neuropathol 2003 Mar; 105(3): 225–32PubMedGoogle Scholar
  35. 35.
    Chen H, Tung YC, Li B, et al. Trophic factors counteract elevated FGF-2-induced inhibition of adult neurogenesis. Neurobiol Aging 2007 Aug; 28(8): 1148–62PubMedCrossRefGoogle Scholar
  36. 36.
    Gschanes A, Windisch M. The influence of Cerebrolysin® and E021 on spatial navigation of 24-month-old rats. J Neural Transm Suppl 1998; 53: 313–21PubMedCrossRefGoogle Scholar
  37. 37.
    Valouskova V, Francis-Turmer L. The short-term influence of b-FGF, NGF and Cerebrolysin® on the memory impaired after fimbria-fornix lesion [abstract]. J Neural Transm Suppl 1996; 47: 280PubMedCrossRefGoogle Scholar
  38. 38.
    Francis-Turner L, Valouskova V, Mokry J. The long-term effect of NGF, b-FGF and Cerebrolysin® on the spatial memory after fimbria-fornix lesion in rats [abstract]. J Neural Transm Suppl 1996; 47: 277PubMedCrossRefGoogle Scholar
  39. 39.
    Valouskova V, Gschanes A. Effects of NGF, b-FGF, and cerebrolysin on water maze performance and on motor activity of rats: short- and long-term study. Neurobiol Learn Mem 1999 Mar; 71(2): 132–49PubMedCrossRefGoogle Scholar
  40. 40.
    Hutter-Paier B, Eggenreich U, Windisch M. Effects of two protein-free peptide derivatives on passive avoidance behaviour of 24-month-old rats. Arzneimittelforschung 1996 Mar; 46(3): 237–41PubMedGoogle Scholar
  41. 41.
    Xiong H, Wojtowicz JM, Baskys A. Brain tissue hydrolysate acts on presynaptic adenosine receptors in the rat hippocampus. Can J Physiol Pharmacol 1995 Aug; 73(8): 1194–7PubMedCrossRefGoogle Scholar
  42. 42.
    Xiong H, Baskys A, Wojtowicz JM. Brain-derived peptides inhibit synaptic transmission via presynaptic GABAB receptors in CA1 area of rat hippocampal slices. Brain Res 1996 Oct 21; 737(1-2): 188–94PubMedCrossRefGoogle Scholar
  43. 43.
    Baskys A, Wojtowicz JM. Effects of brain tissue hydrolysate on synaptic transmission in the hippocampus. Pharmacol Biochem Behav 1994 Dec; 49(4): 1105–7PubMedCrossRefGoogle Scholar
  44. 44.
    Baskys A, Wojtowicz MJ. Actions of organ-derived preparations on synaptic transmission in the hippocampus. Adv Biosci 1993; 87: 345–6Google Scholar
  45. 45.
    Lombardi VRM, Windisch M, García M, et al. Effects of Cerebrolysin® on in vitro primary microglial and astrocyte rat cell cultures. Methods Find Exp Clin Pharmacol 1999; 21(5): 331–8PubMedCrossRefGoogle Scholar
  46. 46.
    Rockenstein E, Adame A, Mante M, et al. Amelioration of the cerebrovascular amyloidosis in a transgenic model of Alzheimer’s disease with the neurotrophic compound Cerebrolysin™. J Neural Transm 2005 Feb; 112(2): 269–82PubMedCrossRefGoogle Scholar
  47. 47.
    Alvarez A, Sampedro C, Cacabelos R, et al. Reduced TNF-alpha and increased IGF-I levels in the serum of Alzheimer patients treated with the neurotrophic agent Cerebrolysin. Int J Neuropsychopharmacol 2009; 12: 867–72PubMedCrossRefGoogle Scholar
  48. 48.
    Alvarez XA, Cacabelos R, Laredo M, et al. A 24-week, double-blind, placebo-controlled study of three dosages of Cerebrolysin in patients with mild to moderate Alzheimer’s disease. Eur J Neurol 2006 Jan; 13(1): 43–54PubMedCrossRefGoogle Scholar
  49. 49.
    Gschanes A, Boado R, Sametz W, et al. The drug cerebrolysin and its peptide fraction E021 increase the abundance of the blood-brain barrier GLUT1 glucose transporter in brains of young and old rats. Histochem J 2000 Feb; 32(2): 71–7PubMedCrossRefGoogle Scholar
  50. 50.
    Boado RJ. Amplification of blood-brain barrier GLUT1 glucose transporter gene expression by brain-derived peptides. Neurosci Res 2001 Aug; 40(4): 337–42PubMedCrossRefGoogle Scholar
  51. 51.
    Frey II WH, Hanson LR, Liu X-F, et al. Quantitative and qualitative distribution of 125I-labeled Cerebrolysin peptides in the CNS following IN delivery. Unterach, Austria: EBEWE Neuro Pharma GmbH, 2005 Jun. (Data on file)Google Scholar
  52. 52.
    Gschanes A, Valouskova V, Windisch M. Ameliorative influence of a nootropic drug on motor activity of rats after bilateral carotid artery occlusion. J Neural Transm 1997; 104(11-12): 1319–27PubMedCrossRefGoogle Scholar
  53. 53.
    Qaseem A, Snow V, Cross Jr JT, et al. Current pharmaco-logic treatment of dementia: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med 2008; 148: 370–8PubMedGoogle Scholar
  54. 54.
    Alvarez XA, Cacabelos R, Sanpedro C, et al. Efficacy and safety of Cerebrolysin in moderate to moderately severe Alzheimer’s disease: results of a randomized, double-blind, controlled trial investigating three dosages of Cerebrolysin. Unterach, Austria: EBEWE Neuro Pharma GmbH, 2009. (Data on file)Google Scholar
  55. 55.
    Bae C-Y, Cho C-Y, Cho K, et al. A double-blind, placebo-controlled, multicenter study of Cerebrolysin for Alzheimer’s disease. J Am Geriatr Soc 2000 Dec; 48(12): 1566–71PubMedGoogle Scholar
  56. 56.
    Panisset M, Gauthier S, Moessler H, et al. Cerebrolysin in Alzheimer’s disease: a randomized, double-blind, placebo-controlled trial with a neurotrophic agent. J Neural Transm 2002 Jul; 109(7-8): 1089–104PubMedCrossRefGoogle Scholar
  57. 57.
    Ruether E, Husmann R, Kinzler E, et al. A 28-week, double-blind, placebo-controlled study with Cerebrolysin in patients with mild to moderate Alzheimer’s disease. Int Clin Psychopharmacol 2001 Sep; 16(5): 253–63PubMedCrossRefGoogle Scholar
  58. 58.
    Ruether E, Alvarez XA, Rainer M, et al. Sustained improvement of cognition and global function in patients with moderately severe Alzheimer’s disease: a double-blind, placebo-controlled study with the neurotrophic agent Cerebrolysin®. J Neural Transm Suppl 2002; 62: 265–75PubMedGoogle Scholar
  59. 59.
    Rüther E, Ritter R, Apecechea M, et al. Sustained improvements in patients with dementia of Alzheimer’s type (DAT) 6 months after termination of Cerebrolysin therapy. J Neural Transm 2000; 107(7): 815–29PubMedCrossRefGoogle Scholar
  60. 60.
    Rüther E, Ritter R, Apecechea M, et al. Efficacy of the peptidergic nootropic drug Cerebrolysin in patients with senile dementia of the Alzheimer type (SDAT). Pharma-copsychiatry 1994 Jan; 27(1): 32–40Google Scholar
  61. 61.
    Xiao S, Yan H, Yao P, et al. Efficacy of FPF 1070 (Cere-brolysin) in patients with Alzheimer’s disease: a multi-centre, randomised, double-blind, placebo-controlled trial. Clin Drug Invest 2000 Jan; 19(1): 43–53CrossRefGoogle Scholar
  62. 62.
    Muresanu DF, Rainer M, Moessler H. Improved global function and activities of daily living in patients with AD: a placebo-controlled clinical study with the neurotrophic agent Cerebrolysin®. J Neural Transm Suppl 2002; 62: 277–285PubMedGoogle Scholar
  63. 63.
    Alvarez A, Cacabelos R, Aleixandre M, et al. Synergistic treatment effects with Cerebrolysin and donepezil: results from a randomized, double-blind, multicenter trial to compare safety and effiacy of Cerebrolysin, donepezil and a combination of both in patients with probable Alzheimer’s disease [abstract]. International Conference on Alzheimer’s Disease; 2009 Jul 11–16; ViennaGoogle Scholar
  64. 64.
    Alvarez XA, Cacabelos R. Integrated clinical study report (protocol EBE031010). A randomized, double-blind, clinical trial to compare the safety and efficacy of a Cerebro-lysin and Aricept (donepezil) and a combination therapy in patients with probable Alzheimer’s disease. Unterach, Austria: EBEWE Neuro Pharma GmbH, 2008 Nov 27. (Data on file)Google Scholar
  65. 65.
    Gavrilova SI, Kolykhalov IV, Korovaitseva GI, et al. ApoE genotype and efficacy of neurotrophic and cholinergic therapy in Alzheimer’s disease [in Russian]. Zh Nevrol Psikhiatr Im SS Korsakova 2005; 105(4): 27–34Google Scholar
  66. 66.
    Wei Z-H, He Q-B, Wang H, et al. Meta-analysis: the efficacy of nootropic agent Cerebrolysin in the treatment of Alzheimer’s disease. J Neural Transm 2007; 114(5): 629–34PubMedCrossRefGoogle Scholar
  67. 67.
    Xiao S, Yan H, Yao P. The efficacy of cerebrolysin in patients with vascular dementia: results of a Chinese multi-centre, randomised, double-blind, placebo-controlled trial. The Cerebrolysin Study Group. Hong Kong J Psychiatry 1999; 9(2): 13–9Google Scholar
  68. 68.
    Vereschagin NV, Nekrasova EM, Lebedova NV, et al. Mild forms of multi-infarct dementia: effectiveness of cere-brolysin [in Russian]. Sov Med 1991; (11): 6–8Google Scholar
  69. 69.
    Guekht A, Moessler H, Doppler E, et al. Cerebrolysin in vascular dementia: improvement of clinical outcome in a randomized, double-blind, placebo-controlled multicenter trial [abstract plus poster]. 9th International Conference for Alzheimer’s and Parkinson’s Disease; 2009 Mar 11–15; PragueGoogle Scholar
  70. 70.
    Gusev EI. Integrated clinical study report (protocol EBE-RU-051201). A randomized, double-blind, placebo-controlled clinical trial to evaluate the safety and efficacy of 20 ml Cerebrolysin in patients with vascular dementia. Unterach, Austria: EBEWE Neuro Pharma GmbH, 2008 Aug 18. (Data on file)Google Scholar
  71. 71.
    Muresanu DF. The influence of Cerebrolysin on cognitive performances in patients suffering from vascular dementia. Unterach, Austria: EBEWE Pharmaceuticals Ltd, 1999Google Scholar
  72. 72.
    Damulin IV, Koberskaya NN, Mkhitaryan EA. Effects of cerebrolysin on moderate cognitive impairments in cerebral vascular insufficiency (a clinical-electrophysiological study). Neurosci Behav Physiol 2008 Jul; 38(6): 639–45PubMedCrossRefGoogle Scholar
  73. 73.
    Muresanu DF, Alvarez XA, Moessler H, et al. A pilot study to evaluate the effects of Cerebrolysin on cognition and qEEG in vascular dementia: cognitive improvement correlates with qEEG acceleration. J Neurol Sci 2008 Apr 15; 267(1-2): 112–9PubMedCrossRefGoogle Scholar
  74. 74.
    Yakhno NN, Damulin IV, Zakharov VV, et al. Use of Cerebrolysin for treatment of vascular dementia [in Russian]. Ter Arkh 1996; 68(10): 65–9Google Scholar
  75. 75.
    Rainer M, Brunnbauer M, Dunky A, et al. Therapeutic results with Cerebrolysin® in the treatment of dementia. Wien Med Wochenschr 1997; 147(18): 426–31PubMedGoogle Scholar
  76. 76.
    Robinson DM, Keating GM. Memantine: a review of its use in Alzheimer’s disease. Drugs 2006; 66(11): 1515–34PubMedCrossRefGoogle Scholar
  77. 77.
    American Psychiatric Association. Practice guideline for the treatment of patients with Alzheimer’s disease and other dementias, second edition [online]. Available from URL: http://www.psychiatryonline.com/pracGuide/loadGuidelinePdf.aspx?file=AlzPG101007 [Accessed 2009 Jul 9]
  78. 78.
    Raina P, Santaguida P, Ismaila A, et al. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med 2008; 148: 379–97PubMedGoogle Scholar
  79. 79.
    Seow D, Gauthier S. Pharmacotherapy of Alzheimer disease. Can J Psychiatry 2007 Oct; 52(10): 620–9PubMedGoogle Scholar
  80. 80.
    Hüll M, Berger M, Heneka M. Disease-modifying therapies in Alzheimer’s disease: how far have we come? Drugs 2006; 66(16): 2075–93PubMedCrossRefGoogle Scholar
  81. 81.
    Wisniewski T, Konietzko U. Amyloid-beta immunisation for Alzheimer’s disease. Lancet Neurol 2008; 7: 805–11PubMedCrossRefGoogle Scholar
  82. 82.
    Molnar FJ, Hutton B, Fergusson D. Does analysis using “last observation carried forward” introduce bias in dementia research? Can Med Assoc J 2008 Oct 7; 179(8): 751–3CrossRefGoogle Scholar
  83. 83.
    Gauthier S, Loft H, Cummings J. Improvement in beha vioural symptoms in patients with moderate to severe Alzheimer’s disease by memantine: a pooled data analysis. Int J Geriatr Psychiatry 2008 May; 23(5): 537–45PubMedCrossRefGoogle Scholar
  84. 84.
    Drijgers RL, Aalten P, Winogrodzka A, et al. Pharmacological treatment of apathy in neurodegenerative diseases: a systematic review. Dement Geriatr Cogn Disord 2009 Jul; 28(1): 13–22PubMedCrossRefGoogle Scholar
  85. 85.
    Frankfort SV, Tulner LR, van Campen JP, et al. Amyloid beta protein and tau in cerebrospinal fluid and plasma as biomarkers for dementia: a review of recent literature. Curr Clin Pharmacol 2008 May; 3(2): 123–31PubMedCrossRefGoogle Scholar
  86. 86.
    Pauwels EK, Volterrani D, Mariani G. Biomarkers for Alzheimer’s disease. Drug News Perspect 2009 Apr; 22(3): 151–60PubMedCrossRefGoogle Scholar
  87. 87.
    Sacchetti B, Lorenzini CA, Baldi E, et al. Pituitary adenylate cyclase-activating polypeptide hormone (PACAP) at very low dosages improves memory in the rat. Neurobiol Learn Mem 2001 Jul; 76(1): 1–6PubMedCrossRefGoogle Scholar
  88. 88.
    Mamounas LA, Altar CA, Blue ME, et al. BDNF promotes the regenerative sprouting, but not survival, of injured serotonergic axons in the adult rat brain. J Neurosci 2000 Jan 15; 20(2): 771–82PubMedGoogle Scholar

Copyright information

© Adis Data Information BV 2009

Authors and Affiliations

  1. 1.Adis, a Wolters Kluwer BusinessMairangi Bay, North Shore 0754, AucklandNew Zealand
  2. 2.McGill Center for Studies in AgingMontréalCanada

Personalised recommendations