Randomized, placebo-controlled, double-blind, pilot trial to investigate safety and efficacy of Cerebrolysin in patients with aneurysmal subarachnoid hemorrhage

Peter Y M Woo, Joanna W K Ho, Natalie M W Ko, Ronald P T Li, Leo Jian, Alberto C H Chu, Marco C L Kwan, Yung Chan, Alain K S Wong, Hoi-Tung Wong, Kwong-Yau Chan, John C K Kwok, Peter Y M Woo, Joanna W K Ho, Natalie M W Ko, Ronald P T Li, Leo Jian, Alberto C H Chu, Marco C L Kwan, Yung Chan, Alain K S Wong, Hoi-Tung Wong, Kwong-Yau Chan, John C K Kwok

Abstract

Asbtract: BACKGROUND: There are limited neuroprotective treatment options for patients with aneurysmal subarachnoid hemorrhage (SAH). Cerebrolysin, a brain-specific proposed pleiotropic neuroprotective agent, has been suggested to improve global functional outcomes in ischemic stroke. We investigated the efficacy, safety and feasibility of administering Cerebrolysin for SAH patients.

Methods: This was a prospective, randomized, double-blind, placebo-controlled, single-center, parallel-group pilot study. Fifty patients received either daily Cerebrolysin (30 ml/day) or a placebo (saline) for 14 days (25 patients per study group). The primary endpoint was a favorable Extended Glasgow Outcome Scale (GOSE) of 5 to 8 (moderate disability to good recovery) at six-months. Secondary endpoints included the modified Ranking Scale (mRS), the Montreal Cognitive Assessment (MOCA) score, occurrence of adverse effects and the occurrence of delayed cerebral ischemia (DCI).

Results: No severe adverse effects or mortality attributable to Cerebrolysin were observed. No significant difference was detected in the proportion of patients with favorable six-month GOSE in either study group (odds ratio (OR): 1.49; 95% confidence interval (CI): 0.43-5.17). Secondary functional outcome measures for favorable six-month recovery i.e. a mRS of 0 to 3 (OR: 3.45; 95% CI 0.79-15.01) were comparable for both groups. Similarly, there was no difference in MOCA neurocognitive performance (p-value: 0.75) and in the incidence of DCI (OR: 0.85 95% CI: 0.28-2.59).

Conclusions: Use of Cerebrolysin in addition to standard-of-care management of aneurysmal SAH is safe, well tolerated and feasible. However, the neutral results of this trial suggest that it does not improve the six-month global functional performance of patients.

Clinical trial registration: Name of Registry: ClinicalTrials.gov Trial Registration Number: NCT01787123 . Date of Registration: 8th February 2013.

Keywords: Aneurysmal subarachnoid hemorrhage; Delayed cerebral ischemia; Neuroprotection.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Trial subject profile
Fig. 2
Fig. 2
Distribution of six-month GOSE and mRS global functional outcomes for Cerebrolysin and saline group subjects
Fig. 3
Fig. 3
Forest plot. A priori subgroup analysis for favorable GOSE (5 to 8) at 6 months. n, number with favorable GOSE in each subgroup. N, total number randomized in each subgroup. TE, treatment effect. WFNS, World Federation of Neurosurgical Societies

References

    1. Johnston SC, Selvin S, Gress DR. The burden, trends, and demographics of mortality from subarachnoid hemorrhage. Neurology. 1998;50(5):1413–1418. doi: 10.1212/wnl.50.5.1413.
    1. Pickard JD, Murray GD, Illingworth R, Shaw MD, Teasdale GM, Foy PM, et al. Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial. BMJ. 1989;298(6674):636–642. doi: 10.1136/bmj.298.6674.636.
    1. Molyneux AJ, Kerr RS, Yu LM, Clarke M, Sneade M, Yarnold JA, et al. International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysm occlusion. Lancet. 2005;366(9488):809–817. doi: 10.1016/S0140-6736(05)67214-5.
    1. Khan AU, Dulhanty L, Vail A, Tyrrell P, Galea J, Patel HC. Impact of specialist neurovascular care in subarachnoid haemorrhage. Clin Neurol Neurosurg. 2015;133:55–60. doi: 10.1016/j.clineuro.2015.03.006.
    1. Vergouwen MD, Vermeulen M, van Gijn J, Rinkel GJ, Wijdicks EF, Muizelaar JP, et al. Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: proposal of a multidisciplinary research group. Stroke. 2010;41(10):2391–2395. doi: 10.1161/STROKEAHA.110.589275.
    1. Frontera JA, Fernandez A, Schmidt JM, Claassen J, Wartenberg KE, Badjatia N, et al. Defining vasospasm after subarachnoid hemorrhage: what is the most clinically relevant definition? Stroke. 2009;40(6):1963–1968. doi: 10.1161/STROKEAHA.108.544700.
    1. Schmidt JM, Wartenberg KE, Fernandez A, Claassen J, Rincon F, Ostapkovich ND, et al. Frequency and clinical impact of asymptomatic cerebral infarction due to vasospasm after subarachnoid hemorrhage. J Neurosurg. 2008;109(6):1052–1059. doi: 10.3171/JNS.2008.109.12.1052.
    1. Budohoski KP, Guilfoyle M, Helmy A, Huuskonen T, Czosnyka M, Kirollos R, et al. The pathophysiology and treatment of delayed cerebral ischaemia following subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry. 2014;85(12):1343–1353. doi: 10.1136/jnnp-2014-307711.
    1. Velat GJ, Kimball MM, Mocco JD, Hoh BL. Vasospasm after aneurysmal subarachnoid hemorrhage: review of randomized controlled trials and meta-analyses in the literature. World Neurosurg. 2011;76(5):446–454. doi: 10.1016/j.wneu.2011.02.030.
    1. Macdonald RL, Kassell NF, Mayer S, Ruefenacht D, Schmiedek P, Weidauer S, et al. Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage (CONSCIOUS-1): randomized, double-blind, placebo-controlled phase 2 dose-finding trial. Stroke. 2008;39(11):3015–3021. doi: 10.1161/STROKEAHA.108.519942.
    1. Kassell NF, Haley EC, Jr, Apperson-Hansen C, Alves WM. Randomized, double-blind, vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: a cooperative study in Europe, Australia, and New Zealand. J Neurosurg. 1996;84(2):221–228. doi: 10.3171/jns.1996.84.2.0221.
    1. van den Bergh WM, Group MS. Algra A, Dorhout Mees SM, van Kooten F, Dirven CM, et al. Randomized controlled trial of acetylsalicylic acid in aneurysmal subarachnoid hemorrhage: the MASH study. Stroke. 2006;37(9):2326–2330. doi: 10.1161/01.STR.0000236841.16055.0f.
    1. Kirkpatrick PJ, Turner CL, Smith C, Hutchinson PJ, Murray GD, Collaborators S. Simvastatin in aneurysmal subarachnoid haemorrhage (STASH): a multicentre randomised phase 3 trial. Lancet Neurol. 2014;13(7):666–675. doi: 10.1016/S1474-4422(14)70084-5.
    1. Wong GK, Poon WS, Chan MT, Boet R, Gin T, Ng SC, et al. Intravenous magnesium sulphate for aneurysmal subarachnoid hemorrhage (IMASH): a randomized, double-blinded, placebo-controlled, multicenter phase III trial. Stroke. 2010;41(5):921–926. doi: 10.1161/STROKEAHA.109.571125.
    1. Egge A, Waterloo K, Sjoholm H, Solberg T, Ingebrigtsen T, Romner B. Prophylactic hyperdynamic postoperative fluid therapy after aneurysmal subarachnoid hemorrhage: a clinical, prospective, randomized, controlled study. Neurosurgery. 2001;49(3):593–605. doi: 10.1097/00006123-200109000-00012.
    1. Zwienenberg-Lee M, Hartman J, Rudisill N, Madden LK, Smith K, Eskridge J, et al. Effect of prophylactic transluminal balloon angioplasty on cerebral vasospasm and outcome in patients with fisher grade III subarachnoid hemorrhage: results of a phase II multicenter, randomized, clinical trial. Stroke. 2008;39(6):1759–1765. doi: 10.1161/STROKEAHA.107.502666.
    1. Dorhout Mees SM, Rinkel GJ, Feigin VL, Algra A, van den Bergh WM, Vermeulen M, et al. Calcium antagonists for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev. 2007;3:CD000277. doi: 10.1002/14651858.CD000277.pub3.
    1. Zhang L, Chopp M, Meier DH, Winter S, Wang L, Szalad A, et al. Sonic hedgehog signaling pathway mediates cerebrolysin-improved neurological function after stroke. Stroke. 2013;44(7):1965–1972. doi: 10.1161/STROKEAHA.111.000831.
    1. Zhang L, Chopp M, Wang C, Zhang Y, Lu M, Zhang T, et al. Prospective, double blinded, comparative assessment of the pharmacological activity of Cerebrolysin and distinct peptide preparations for the treatment of embolic stroke. J Neurol Sci. 2019;398:22–26. doi: 10.1016/j.jns.2019.01.017.
    1. Zhang C, Chopp M, Cui Y, Wang L, Zhang R, Zhang L, et al. Cerebrolysin enhances neurogenesis in the ischemic brain and improves functional outcome after stroke. J Neurosci Res. 2010;88(15):3275–3281. doi: 10.1002/jnr.22495.
    1. Schauer E, Wronski R, Patockova J, Moessler H, Doppler E, Hutter-Paier B, et al. Neuroprotection of cerebrolysin in tissue culture models of brain ischemia: post lesion application indicates a wide therapeutic window. J Neural Transm (Vienna) 2006;113(7):855–868. doi: 10.1007/s00702-005-0384-3.
    1. Ren J, Sietsma D, Qiu S, Moessler H, Finklestein SP. Cerebrolysin enhances functional recovery following focal cerebral infarction in rats. Restor Neurol Neurosci. 2007;25(1):25–31.
    1. Riley C, Hutter-Paier B, Windisch M, Doppler E, Moessler H, Wronski R. A peptide preparation protects cells in organotypic brain slices against cell death after glutamate intoxication. J Neural Transm (Vienna) 2006;113(1):103–110. doi: 10.1007/s00702-005-0302-8.
    1. Hartbauer M, Hutter-Paie B, Windisch M. Effects of Cerebrolysin on the outgrowth and protection of processes of cultured brain neurons. J Neural Transm (Vienna) 2001;108(5):581–592. doi: 10.1007/s007020170058.
    1. Hartbauer M, Hutter-Paier B, Skofitsch G, Windisch M. Antiapoptotic effects of the peptidergic drug cerebrolysin on primary cultures of embryonic chick cortical neurons. J Neural Transm (Vienna) 2001;108(4):459–473. doi: 10.1007/s007020170067.
    1. Hanson LR, Liu XF, Ross TM, Doppler E, Zimmermann-Meinzingen S, Moessler H. Cerebrolysin reduces infarct volume in a rat model of focal cerebral ischemic damage. Am J Neuroprotec Neurogen. 2009;1:62–68.
    1. Gutmann B, Hutter-Paier B, Skofitsch G, Windisch M, Gmeinbauer R. In vitro models of brain ischemia: the peptidergic drug cerebrolysin protects cultured chick cortical neurons from cell death. Neurotox Res. 2002;4(1):59–65. doi: 10.1080/10298420290007637.
    1. Catalin B, Rogoveanu OC, Pirici I, Balseanu TA, Stan A, Tudorica V, et al. Cerebrolysin and aquaporin 4 inhibition improve pathological and motor recovery after ischemic stroke. CNS Neurol Disord Drug Targets. 2018;17(4):299–308. doi: 10.2174/1871527317666180425124340.
    1. Doppler E, Rockenstein E, Ubhi K, Inglis C, Mante M, Adame A, et al. Neurotrophic effects of Cerebrolysin in the Mecp2(308/Y) transgenic model of Rett syndrome. Acta Neuropathol. 2008;116(4):425–437. doi: 10.1007/s00401-008-0407-x.
    1. Guan X, Wang Y, Kai G, Zhao S, Huang T, Li Y, et al. Cerebrolysin ameliorates focal cerebral ischemia injury through Neuroinflammatory inhibition via CREB/PGC-1alpha pathway. Front Pharmacol. 2019;10:1245. doi: 10.3389/fphar.2019.01245.
    1. Baskys A, Wojtowicz JM. Effects of brain tissue hydrolysate on synaptic transmission in the hippocampus. Pharmacol Biochem Behav. 1994;49(4):1105–1107. doi: 10.1016/0091-3057(94)90272-0.
    1. Muresanu DF, Heiss WD, Hoemberg V, Bajenaru O, Popescu CD, Vester JC, et al. Cerebrolysin and recovery after stroke (CARS): a randomized, placebo-controlled, double-blind, multicenter trial. Stroke. 2016;47(1):151–159. doi: 10.1161/STROKEAHA.115.009416.
    1. Xue LX, Zhang T, Zhao YW, Geng Z, Chen JJ, Chen H. Efficacy and safety comparison of DL-3-n-butylphthalide and Cerebrolysin: effects on neurological and behavioral outcomes in acute ischemic stroke. Exp Ther Med. 2016;11(5):2015–2020. doi: 10.3892/etm.2016.3139.
    1. Lang W, Stadler CH, Poljakovic Z, Fleet D, Lyse SG. A prospective, randomized, placebo-controlled, double-blind trial about safety and efficacy of combined treatment with alteplase (rt-PA) and Cerebrolysin in acute ischaemic hemispheric stroke. Int J Stroke. 2013;8(2):95–104. doi: 10.1111/j.1747-4949.2012.00901.x.
    1. Chang WH, Park CH, Kim DY, Shin YI, Ko MH, Lee A, et al. Cerebrolysin combined with rehabilitation promotes motor recovery in patients with severe motor impairment after stroke. BMC Neurol. 2016;16:31. doi: 10.1186/s12883-016-0553-z.
    1. Gharagozli K, Harandi AA, Houshmand S, Akbari N, Muresanu DF, Vester J, et al. Efficacy and safety of Cerebrolysin treatment in early recovery after acute ischemic stroke: a randomized, placebo-controlled, double-blinded, multicenter clinical trial. J Med Life. 2017;10(3):153–160.
    1. Amiri-Nikpour MR, Nazarbaghi S, Ahmadi-Salmasi B, Mokari T, Tahamtan U, Rezaei Y. Cerebrolysin effects on neurological outcomes and cerebral blood flow in acute ischemic stroke. Neuropsychiatr Dis Treat. 2014;10:2299–2306. doi: 10.2147/NDT.S75304.
    1. Ziganshina LE, Abakumova T, Vernay L. Cerebrolysin for acute ischaemic stroke. Cochrane Database Syst Rev. 2017;4:CD007026. doi: 10.1002/14651858.CD007026.pub5.
    1. Guekht A, Vester J, Heiss WD, Gusev E, Hoemberg V, Rahlfs VW, et al. Safety and efficacy of Cerebrolysin in motor function recovery after stroke: a meta-analysis of the CARS trials. Neurol Sci. 2017;38(10):1761–1769. doi: 10.1007/s10072-017-3037-z.
    1. Bornstein NM, Guekht A, Vester J, Heiss WD, Gusev E, Homberg V, et al. Safety and efficacy of Cerebrolysin in early post-stroke recovery: a meta-analysis of nine randomized clinical trials. Neurol Sci. 2018;39(4):629–640. doi: 10.1007/s10072-017-3214-0.
    1. Wang Z, Shi L, Xu S, Zhang J. Cerebrolysin for functional recovery in patients with acute ischemic stroke: a meta-analysis of randomized controlled trials. Drug Des Devel Ther. 2017;11:1273–1282. doi: 10.2147/DDDT.S124273.
    1. Zhang D, Dong Y, Li Y, Chen J, Wang J, Hou L. Efficacy and safety of Cerebrolysin for acute ischemic stroke: a meta-analysis of randomized controlled trials. Biomed Res Int. 2017;2017:4191670. doi: 10.1155/2017/4191670.
    1. Park YK, Yi HJ, Choi KS, Lee YJ, Kim DW, Kwon SM. Cerebrolysin for the treatment of aneurysmal subarachnoid hemorrhage in adults: a retrospective chart review. Adv Ther. 2018;35(12):2224–2235. doi: 10.1007/s12325-018-0832-8.
    1. Heiss WD, Brainin M, Bornstein NM, Tuomilehto J, Hong Z. Cerebrolysin Acute Stroke Treatment in Asia I. Cerebrolysin in patients with acute ischemic stroke in Asia: results of a double-blind, placebo-controlled randomized trial. Stroke. 2012;43(3):630–636. doi: 10.1161/STROKEAHA.111.628537.
    1. Ladurner G, Kalvach P, Moessler H, Cerebrolysin Study G Neuroprotective treatment with cerebrolysin in patients with acute stroke: a randomised controlled trial. J Neural Transm (Vienna) 2005;112(3):415–428. doi: 10.1007/s00702-004-0248-2.
    1. Weir B, Grace M, Hansen J, Rothberg C. Time course of vasospasm in man. J Neurosurg. 1978;48(2):173–178. doi: 10.3171/jns.1978.48.2.0173.
    1. Connolly ES, Jr, Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, Higashida RT, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/american Stroke Association. Stroke. 2012;43(6):1711–1737. doi: 10.1161/STR.0b013e3182587839.
    1. Sano H, Inamasu J, Kato Y, Satoh A, Murayama Y, Diseases WC, et al. Modified world federation of neurosurgical societies subarachnoid hemorrhage grading system. Surg Neurol Int. 2016;7(Suppl 18):S502–S503. doi: 10.4103/2152-7806.187491.
    1. Suarez JI, Sheikh MK, Macdonald RL, Amin-Hanjani S, Brown RD, Jr, de Oliveira Manoel AL, et al. Common data elements for Unruptured intracranial aneurysms and subarachnoid hemorrhage clinical research: a National Institute for neurological disorders and stroke and National Library of medicine project. Neurocrit Care. 2019;30(Suppl 1):4–19. doi: 10.1007/s12028-019-00723-6.
    1. Lantigua H, Ortega-Gutierrez S, Schmidt JM, Lee K, Badjatia N, Agarwal S, et al. Subarachnoid hemorrhage: who dies, and why? Crit Care. 2015;19:309. doi: 10.1186/s13054-015-1036-0.
    1. Fischer U, Arnold M, Nedeltchev K, Schoenenberger RA, Kappeler L, Hollinger P, et al. Impact of comorbidity on ischemic stroke outcome. Acta Neurol Scand. 2006;113(2):108–113. doi: 10.1111/j.1600-0404.2005.00551.x.
    1. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373–383. doi: 10.1016/0021-9681(87)90171-8.
    1. Frontera JA, Claassen J, Schmidt JM, Wartenberg KE, Temes R, Connolly ES, Jr, et al. Prediction of symptomatic vasospasm after subarachnoid hemorrhage: the modified fisher scale. Neurosurgery. 2006;59(1):21–27. doi: 10.1227/01.NEU.0000218821.34014.1B.
    1. Hijdra A, Brouwers PJ, Vermeulen M, van Gijn J. Grading the amount of blood on computed tomograms after subarachnoid hemorrhage. Stroke. 1990;21(8):1156–1161. doi: 10.1161/01.STR.21.8.1156.
    1. Woo PYM, Tse TPK, Chan RSK, Leung LNY, Liu SKK, Leung AYT, et al. Computed tomography interobserver agreement in the assessment of aneurysmal subarachnoid hemorrhage and predictors for clinical outcome. J Neurointerv Surg. 2017;9(11):1118–1124. doi: 10.1136/neurintsurg-2016-012576.
    1. Stienen MN, Visser-Meily JM, Schweizer TA, Hanggi D, Macdonald RL, Vergouwen MDI, et al. Prioritization and timing of outcomes and endpoints after aneurysmal subarachnoid hemorrhage in clinical trials and observational studies: proposal of a multidisciplinary research group. Neurocrit Care. 2019;30(Suppl 1):102–113. doi: 10.1007/s12028-019-00737-0.
    1. Uyttenboogaart M, Stewart RE, Vroomen PC, De Keyser J, Luijckx GJ. Optimizing cutoff scores for the Barthel index and the modified Rankin scale for defining outcome in acute stroke trials. Stroke. 2005;36(9):1984–1987. doi: 10.1161/01.STR.0000177872.87960.61.
    1. Andersen CR, Fitzgerald E, Delaney A, Finfer S. A systematic review of outcome measures employed in aneurysmal subarachnoid hemorrhage (aSAH) clinical research. Neurocrit Care. 2019;30(3):534–541. doi: 10.1007/s12028-018-0566-0.
    1. Onose G, Muresanu DF, Ciurea AV, Daia Chendreanu C, Mihaescu AS, Mardare DC, et al. Neuroprotective and consequent neurorehabilitative clinical outcomes, in patients treated with the pleiotropic drug cerebrolysin. J Med Life. 2009;2(4):350–360.
    1. Stallard N. Optimal sample sizes for phase II clinical trials and pilot studies. Stat Med. 2012;31(11–12):1031–1042. doi: 10.1002/sim.4357.
    1. Sim J, Lewis M. The size of a pilot study for a clinical trial should be calculated in relation to considerations of precision and efficiency. J Clin Epidemiol. 2012;65(3):301–308. doi: 10.1016/j.jclinepi.2011.07.011.
    1. Weir J, Steyerberg EW, Butcher I, Lu J, Lingsma HF, McHugh GS, et al. Does the extended Glasgow outcome scale add value to the conventional Glasgow outcome scale? J Neurotrauma. 2012;29(1):53–58. doi: 10.1089/neu.2011.2137.
    1. Schulz KF, Altman DG, Moher D, Group C CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340:c332. doi: 10.1136/bmj.c332.
    1. McHugh GS, Butcher I, Steyerberg EW, Marmarou A, Lu J, Lingsma HF, et al. A simulation study evaluating approaches to the analysis of ordinal outcome data in randomized controlled trials in traumatic brain injury: results from the IMPACT project. Clin Trials. 2010;7(1):44–57. doi: 10.1177/1740774509356580.
    1. Sandset EC, Bath PM, Boysen G, Jatuzis D, Korv J, Luders S, et al. The angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomised, placebo-controlled, double-blind trial. Lancet. 2011;377(9767):741–750. doi: 10.1016/S0140-6736(11)60104-9.
    1. Ilodigwe D, Murray GD, Kassell NF, Torner J, Kerr RS, Molyneux AJ, et al. Sliding dichotomy compared with fixed dichotomization of ordinal outcome scales in subarachnoid hemorrhage trials. J Neurosurg. 2013;118(1):3–12. doi: 10.3171/2012.9.JNS111383.
    1. Yang Y, Zhang Y, Wang Z, Wang S, Gao M, Xu R, et al. Attenuation of acute phase injury in rat intracranial hemorrhage by Cerebrolysin that inhibits brain edema and inflammatory response. Neurochem Res. 2016;41(4):748–757. doi: 10.1007/s11064-015-1745-4.
    1. Gladstone DJ, Black SE, Hakim AM, Heart, Stroke Foundation of Ontario Centre of Excellence in Stroke R Toward wisdom from failure: lessons from neuroprotective stroke trials and new therapeutic directions. Stroke. 2002;33(8):2123–2136. doi: 10.1161/01.STR.0000025518.34157.51.
    1. Tuttolomondo A, Pecoraro R, Arnao V, Maugeri R, Iacopino DG, Pinto A. Developing drug strategies for the neuroprotective treatment of acute ischemic stroke. Expert Rev Neurother. 2015;15(11):1271–1284. doi: 10.1586/14737175.2015.1101345.
    1. Shamalov NA, Stakhovskaia LV, Burenchev DV, Kichuk IV, Tvorogova TV, Botsina A, et al. The effect of cerebrolysin in dosage 50 ml on the volume of lesion in ischemic stroke. Zh Nevrol Psikhiatr Im S S Korsakova. 2010;110(12 Pt 2):34–37.
    1. Skvortsova VI, Stakhovskaia LV, Gubskii LV, Shamalov NA, Tikhonova IV, Smychkov AS. A randomized, double-blind, placebo-controlled study of Cerebrolysin safety and efficacy in the treatment of acute ischemic stroke. Zh Nevrol Psikhiatr Im S S Korsakova. 2004;(Suppl 11):51–5.
    1. Al-Mufti F, Amuluru K, Changa A, Lander M, Patel N, Wajswol E, et al. Traumatic brain injury and intracranial hemorrhage-induced cerebral vasospasm: a systematic review. Neurosurg Focus. 2017;43(5):E14. doi: 10.3171/2017.8.FOCUS17431.
    1. Khalili H, Niakan A, Ghaffarpasand F. Effects of cerebrolysin on functional recovery in patients with severe disability after traumatic brain injury: a historical cohort study. Clin Neurol Neurosurg. 2017;152:34–38. doi: 10.1016/j.clineuro.2016.11.011.
    1. Poon W, Matula C, Vos PE, Muresanu DF, von Steinbuchel N, von Wild K, et al. Safety and efficacy of Cerebrolysin in acute brain injury and neurorecovery: CAPTAIN I-a randomized, placebo-controlled, double-blind, Asian-Pacific trial. Neurol Sci. 2020;41(2):281–293. doi: 10.1007/s10072-019-04053-5.
    1. Ginsberg MD. Current status of neuroprotection for cerebral ischemia: synoptic overview. Stroke. 2009;40(3 Suppl):S111–S114. doi: 10.1161/STROKEAHA.108.528877.
    1. Chen S, Feng H, Sherchan P, Klebe D, Zhao G, Sun X, et al. Controversies and evolving new mechanisms in subarachnoid hemorrhage. Prog Neurobiol. 2014;115:64–91. doi: 10.1016/j.pneurobio.2013.09.002.
    1. Ayer R, Zhang J. Connecting the early brain injury of aneurysmal subarachnoid hemorrhage to clinical practice. Turk Neurosurg. 2010;20(2):159–166. doi: 10.5137/1019-5149.JTN.2714-09.0.
    1. Alvarez XA, Cacabelos R, Sampedro C, Aleixandre M, Linares C, Granizo E, 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. Eur J Neurol. 2011;18(1):59–68. doi: 10.1111/j.1468-1331.2010.03092.x.
    1. Wostrack M, Sandow N, Vajkoczy P, Schatlo B, Bijlenga P, Schaller K, et al. Subarachnoid haemorrhage WFNS grade V: is maximal treatment worthwhile? Acta Neurochir. 2013;155(4):579–586. doi: 10.1007/s00701-013-1634-z.
    1. van Donkelaar CE, Bakker NA, Veeger NJ, Uyttenboogaart M, Metzemaekers JD, Eshghi O, et al. Prediction of outcome after subarachnoid hemorrhage: timing of clinical assessment. J Neurosurg. 2017;126(1):52–59. doi: 10.3171/2016.1.JNS152136.
    1. Wong GK, Lam SW, Ngai K, Wong A, Siu D, Poon WS, et al. Cognitive domain deficits in patients with aneurysmal subarachnoid haemorrhage at 1 year. J Neurol Neurosurg Psychiatry. 2013;84(9):1054–1058. doi: 10.1136/jnnp-2012-304517.
    1. Chu AC, Wong GK, Lam SW, Wong A, Ngai K, Poon WS, et al. Cognitive impairment in aneurysmal subarachnoid hemorrhage patients with delayed cerebral infarction: prevalence and pattern. Acta Neurochir Suppl. 2015;120:303–306. doi: 10.1007/978-3-319-04981-6_51.
    1. Chen N, Yang M, Guo J, Zhou M, Zhu C, He L. Cerebrolysin for vascular dementia. Cochrane Database Syst Rev. 2013;1:CD008900. doi: 10.1002/14651858.CD008900.pub2.
    1. Gauthier S, Proano JV, Jia J, Froelich L, Vester JC, Doppler E. Cerebrolysin in mild-to-moderate Alzheimer's disease: a meta-analysis of randomized controlled clinical trials. Dement Geriatr Cogn Disord. 2015;39(5–6):332–347. doi: 10.1159/000377672.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner