Pharmacological Aspects of Neurorehabilitation

Abstract

Physicians in neurorehabilitation often deal with pharmacological problems, marshalling antihypertensive, anticonvulsive and anticoagulation treatments. In addition, there is growing interest in positive or negative effects of medication on brain recovery. Of great importance is the concept of so-called “detrimental drugs” known to negatively influence processes of brain reorganization and recovery. To this group belong anti-convulsive agents such as phenytoin and barbiturates as well as benzodiazepines, butyrophynones and the antihypertensives clonidine and prazosine. Whenever possible these drugs should be avoided in the course of brain recovery after a cerebral lesion.

For only two substances (the SSRI fluoxetine and cerebrolysin, a mixture of pleotropic neuropeptides and amino acids) large randomized controlled trials showed a positive influence on facilitating motor recovery after the stroke. Both substances probably work through pleotropic multiple molecular mechanisms and not as a one-to-one agonist on the receptor. In general the use of antidepressive agents especially SSRI after the stroke can also be recommended for non-depressed stroke patients.

Also dopaminergic drugs have been shown in smaller studies to positively influence functional recovery. Considering their low side-effect profile, the tentative use of 100 mg of L-Dopa per day in the subacute phase of the stroke can be recommended. In MS patients the use of antidepressive agents is also recommend to improve life quality.

In patients with diminished states of consciousness amantadine is the only substance which a randomized controlled study proved to have at least some transient effect. The use of amantadine can be recommended for the improvement of the level of consciousness in these patients.

Key words

neurorehabilitation - pharmacology - brain recovery - neuroprotection - detrimental drugs

• References

• 1 Meyer PM, Hotel JA, Meyer DR. Effects of dl-amphetamine upon placing responses in neodecorticate cats. J Comp Physiol Psychol 1963; 56: 402-404
• 2 Beeney DM, Gonzalez A, Law WA. Amphetamine restores locomotor function after motor cortex injury in the rat. Proc West Parmacol Soc 1981; 24: 15-17
• 3 Hovda DA, Feeney DM. Amphetamine with experience promotes recovery of locomotor function after unilateral frontal cortex injury in the cat. Brain Res 1984; 298: 358-361
• 4 Sutton RL, Feeney Dm. a-Noraderenergic agonists and antagonists affect recovery and maintenance of beam-walking ability after sensorimotor cortex ablation the rat. Restaurative Neurology and Neuroscience 1992; 4: 1-11
• 5 Stroemer RP, Kent TA, Huelebosch CE. Enhanced neocortical neural sprouting, synaptogenesis, and behavioural recovery with D-amphetamine therapy after neocortical infartion in rats. Stroke 1998; 29: 2381-2395
• 6 Hovda DA, Feeney DM. Haloperidol blocks amphetamine induced recovery of binocular depth perception after bilateral visual cortex ablation in the cat. Proc West Pharmacol Soc 1985; 28: 209-211
• 7 Feeney DM, Hovda DA. Reinstatement of binocular depth perception. Brain Res 1985; 342: 352-356
• 8 Hovda DA, Sutton RL, Feeney DM. Amphetamine induced recovery of visual clift performance after bilateral visual cortex ablation in cats: Measurements of. Behav Neurosci 1989; 103: 574-584
• 9 Feeney DM, Gonzalez A, Law WA. Amphetamine, haloperidol and experience interact to affect rate of recovery after motor cortex injury. Science 1982; 217: 855-857
• 10 Hovda DA, Feeney DM. Haloperidol blocks amphetamine induced recovery of binocular depth perception after bilateral visual cortex ablation in the cat. Proc West Pharmacol Soc 1985; 28: 209-211
• 11 Goldstein LB, Davis JN. Post lesion practice and amphetamine-facilitated recovery of beam-walking in the rat. Restor Neurol Neurosci 1990; 2: 311-314
• 12 Plewnia C, Hoppe J, cohen LG. et al. Improved motor skill acquisition after selective stimulation of central norepinephrine. Neurology 2004; 62-2124-2126
• 13 Feeney DM, Westerberg VS. Norepinephrine and brain damage: alpha noradrenergic pharmacology alters functional recovery after cortical trauma. Can J Psychol 1990; 44: 233-252
• 14 Goldstein LB, Davis JN. Clonidine impairs recovery of beam-walking in rats. Brain Res 1990; 508: 305-309
• 15 Stephens J, Goldberg G, Demopoulos JT. Clonidine reinstates deficits following recovery from sensorimonor cortex lesion in rats. Arch Phys Med Rehabil 1986; 67: 666-667
• 16 Baviera M, Invernizzi RW, Carli M. Haloperidol and clozapine have dissociable effects in a model of attentional performance deficits induced by blockade of NMDA receptors in the mPFC. Psychopharmacology (Gerl) 2008; 196: 269-280
• 17 Goldstein LB, Bullman S. Differential effects of haloperidol and clozapine on motor recovery after sensorimontor cortex injury in rats. Neurorehabil neural Repair 2002; 16: 321-325
• 18 Pariente J, Loubinoux I, Carel C. et al. Fluoxetine modulates performance and cerebral activation of patiens recovering from stroke. Ann Neurol 2001; 50: 718-729
• 19 Chweh AQ, Swinyard EA, Wolf HH. Involvement of a GABAergic mechanism in the pharmacologic action of phenytoin. Pharmacol. Biochem Behav 1986; 24: 1301-1304
• 20 Schallert T, Jones TA, Weaver MX. et al. Pharmacologic and anatomic considerations in recovery of function. Phys Med Rehabil 1992; 6: 375-393
• 21 Schallert T, Hernandez TD, Barth TM. Recovery of function after brain damage: Severe and chronic disruption by diazepam. Brain Res 1986; 379: 104-11
• 22 Brailowsky S, Knight RT, Efron R. Phenytoin increases the severity of cortical hemiplegia in rats. Brain Res 1986; 376: 71-77
• 23 Watson CW, Kennard MA. The effect of anticonvulsant drugs on recovery of function following cerebral cortical lesions. J. Neurophysiol 1945; 8: 221-231
• 24 Chweh AQ, Swinyard EA, Wolf HH. Involvement of a GABAergic mechanism in the pharmacologic action of phenytoin. Pharmacol. Biochem Behav 1986; 24: 1301-1304
• 25 Hernandez TD, Holling LC. Disruption of behavioural recovery by the anti-convulsant Phenobarbital. Brain Res 1994; 635: 300-306
• 26 Gold P, Delanoy R, Merrin J. Modulation of long-term potentiation by peripherally administered amphetamine and epinephrine. Brain Res 1984; 305: 103-107
• 27 Goldstein LB. Influence of common drugs and related factors on stroke outcome. Curr Opin Neurol 1997; 10: 52-57
• 28 Bütefish CM, Davis BC, Sawaki L. et al. Modulation of use-dependent plasticity by d-amphetamine. Ann Neurol 2002; 51: 59-68
• 29 Dinse HR, Ragert P, Pleger B. et al. Pharmacological modulation of perceptual learning and associated cortical reorganization. Science 2003; 301: 91-94
• 30 Crisostomo EA, Duncan PW, Propst M. et al. Evidence that amphetamine with physical therapy promotes recovery of motor function in stroke patients. Ann Neurol 1988; 23: 94-97
• 31 Gladstone D, Danells C, Armest A. et al. Physiotherapy coupled with dextroamphetamine for rehabilitation after hemiparetic stroke: A randomized, double-blind, placebo controlled trial. Stroke 2006; 37: 179-185
• 32 Gladstone D, Danells C, Armesto A. et al. Physiotherapy coupled with dextroamphetamine for rehabilitation after hemiparetic stroke. Stroke 2006; 179-185
• 33 Martinsson L, Eksborg S, Wahlgren N. Intensive early physiotherapy combined with dexamphetamine treatment in severe stroke: A randomized, controlled pilot study. Cerebrovasc Dis 2003; 16: 338-345
• 34 Martinsson L, Wahlgren NG. Safety of dexamphetamine in acute ischemic stroke. Stroke 2003; 475-481
• 35 Mazagri R, Shuaib A, McPehrson M. et al. Amphetamine failed to improve motor function in acute stroke. Can J Neurol Sci 1995; 22: S25
• 36 Pla T, Kim IH, Engel U. et al. Amphetamine fails to facilitate motor performance and to enhance motor recovery among stroke patients with mild arm paresis: interim analysis and termination of a double blind, randomised, placebo-controlled trial. Restor Neurol. Neurscience 2005; 23: 271-280
• 37 Sonde L, Lökk J. Effects of amphetamine and/or L-dopa and physiotherapy after stroke – a blinded randomized study. Acta Neurol Scand 2007; 115: 55-59
• 38 Sonde L, Nordström M. Nilsson et al A double blind placebo-controlled study of the effects of amphetamine and physiotherapy after stroke. Cerebrovasc Dis 2001; 1: 253-257
• 39 Treig T, Werner C, Sachse M. et al. No benefit from D-amphetamine when added to physiotherapy after stroke: A randomized, placebo-controlled study. Clin Rehabil 2003; 17: 590-599
• 40 Vachalthiti R, Asavavallobh C, Nilanont Y. et al. Comparison of physical therapy and physical therapy with amphetamine in sonsorimotor recovery of acute stroke patiens: randomized controlled trial. J Neurol Sci 2001; 187 (Suppl. 01) S253
• 41 Walker-Batson D, Smith P. et al. Amphetamine paired with physical therapy accelerates motor recovery after stroke, further evidence. Stroke 1995; 26: 2254-2259
• 42 Walker-Batson D, Smith P. et al. Amphetamine paired with physical therapy accelerates motor recovery after stroke, further evidence. Stroke 1995; 26: 2254-2259
• 43 Scheidtmann K, Fries W, Müller F et al. Effect of levodopa in combination with physiotherapy on functional motor recovery after stroke: A prospective, randomised, double-blind study. Lancet 2003
• 44 Cramer SC, Dobkin Bh, Noser EA. et al. Randomized, placebo-controlled, double-blind study of ropinirole in chronic stroke. Stroke 2009; 40: 3034-3038
• 45 Breitenstein C, Flöer A, Korsukeweitz C. et al. A shift of paradigm: From noradrenergic to dopaminergic modulation of learning?. J Neurol Sci 2006; 248: 42-47
• 46 Seniow J, Litwin T, Lesniak M. et al. New aproach to the rehabilitation of post-stroke focal cognitive syndrome: Effect of levodopa combined with speech and language therapy on functional recovery from aphasia. J Neurol 2009; 283: 214-218
• 47 Leeman B, Laganaro M, Chetelat-Mabillard D. et al. Crossover trial of subacute computerized aphasia therapy for anomia with the addition of either levodopa or placebo. Neurorehabil Neural Repair 2011; 25: 43
• 48 Restemeyer C, Weiller C, Liepert J. No effect of a levodopa single dose on motor performance and motor excitability in chronic stroke. A double-blind placebo controlled cross over pilot study. Restor Neurol Neurosci 2007; 25: 143-150
• 49 Lokk J, Salman Roghani R, Delbani A. Effect of methylphenidate and/or levodopa coupled with physiotherapy on functional and motor recovery after stroke – a randomized, double-blind, placebo-controlled trial. Acta Neurol Scand 2010
• 50 Masihuzzaman AM, Uddin MJ, Majumder S. et al Effect of low dose levodopa on motor outcome of different types of stroke. Mymensingh Med J 2011; 20: 689-693
• 51 Acler M, Fiaschi A, Manganotti P. Long-term levodopa administration in chronic stroke patients: A clinical and neurophysiologic single-blind placebo-controlled cross-over pilot study. Restor Neurol Neurosci 2009; 27: 277-283
• 52 Rosser N, Heuschmann P, Wersching H. et al Levodopa improves procedural motor learning in chronic stroke patients. Arch Phys Med Rehabil 2008; 89: 1633-1641
• 53 Floel A, Breitenstein C, Hummel F. et al Dopaminergic influences on formation of a motor memory. Ann Nerol 2005; 58: 121-130
• 54 Kakuda W, Abo M, Kobayashi K. et al Combination treatment of low-frequency rTMS and occupational therapy with levodopa administration: An intensive neurorehabilitative approach for upper limb hemiparesis after stroke. Int J Neorosci 2011; 121: 373-378
• 55 Tran DA, Pajaro-Blazquez M, Daneault J. et al Combining dopaminergic facilitation with robot-assisted upper limb therapy in stroke survivors: A focused review. Am J Phys Med Rehabil 2016; 95: 459-474
• 56 Zittel S, Weiller C, Liepert J. Reboxetine improves motor function in chronic stroke. A pilot study. J Neurol 2007; 254: 197-201
• 57 Wang LE, Fink GR, Diekhoff S. et al. Noradrenergic enhancement improves motor network connectivity in stroke patients. Ann Neurol 2011; 69: 375-388
• 58 Grade C, Redford B, Chrostowski J. et al. Methylphenidate in early poststroke recovery: A double-blind, placebo-controlled study. Arch Phys Med Rheabil 1998; 79: 1047-1050
• 59 Plenger PM, Dixon CE, Castillo RM. et.al. Subacute methylphenidate treatment for moderate to moderately severe traumatic brain injury: A preliminary double blind placebo-controlled study. Arch Phys Med Rehabil 1996; 77: 536-540
• 60 Whyte J, Hart T, Schuster K. et al. Effects of methylphenidate on attentional function after traumatic brain injury. A randomized, placebo controlled trial. Am J Phys Med Rehabil 1997; 76: 440-450
• 61 Whyte J, Hart T, Vaccaro M. et al. Effects of methylphenidate on attention deficits after traumatic brain injury. A multidiemsional, randomized, controlled trial. Am J Phys Med Rehabil 2004; 83: 401-420
• 62 Kornhuber J, Weller M, Schoppmeyer K. et al. Amantadine and memantine are NMDA receptor antagonists with neuroprotective properties. J Neural Transm Suppl. 1994; 43: 91-104
• 63 Dolin R, Reichman RC, Madore P. et al. A controlled trial of amantadine and rimantadine in the prophylaxis of influenza A infection. N Engl J Med 1982; 10: 580-583
• 64 Schwab R, Poskanzer D, England A. et al Amantadine in Parkinson’s disease. JAMA 1972; 222: 792-795
• 65 Nickels JL, Schneider WN, Dombovy ML. et al. Clinical use of amantadine in brain injury rehabilitation. Brain Inj 1994; 8: 709-718
• 66 Kraus MF, Maki PM. Effect of amantadine hydrochloride on symptoms of frontal lobe dysfunction in brain injury: case studies and review. J Neuropsychiatry Clin Neurosci 1997; 9: 222-230
• 67 Kraus M, Smith G, Butters M. et al. Effects of the dopaminergic agent and NMDA receptor antagonist amantadine on cognitive function, cerebral glucose metabolism and D2 receptor availability in chronic traumatic brain injury: A study using positron emission tomography (PET). Brain Inj 2005; 19: 471-479
• 68 Leone H, Polsonetti BW. Amantadine for traumatic brain injury: does it improve cognition and reduce agitation?. J Clin Pharm Ther 2005; 30: 101-104
• 69 Schneider WN, Drew Cates J, Wong TM. et al Cognitive and behavioural efficacy of amantadine in acute traumatic brain injury: an initital double-blind placebo-controlled study. Brain Inj 1999; 13: 863-872
• 70 Sawyer E, Mauro LS, Ohlinger MU. Amantadine for traumatic brain injury: does it improve cognition and reduce agitation?. J Clin Pharm Ther 2006; 30: 101-104
• 71 Giacino J, Whyte J, Bagierlla E. et al. Placebo-controlled trial of amantadine for severe traumatic brain injury. N Engl J Med 2012; 366: 819-826
• 72 Hammond FM, Sherer M, Malec JF. et al. Amantadine effect on perceptions of irritability after traumatic brain injury: Results of the Amantadine Irritability Multisite Study. J Neurotrauma 2015; 32: 1230-1238
• 73 Huber W, Willmes K, Poeck K. et al. Piracetam as an adjuvant to language therapy for aphasia: A randomized double-blind placebo-controlled pilot study. Arch Phys Med Rehabil 1997; 78: 245-250
• 74 Kessler J, Thiel A, Karbe H. et al. Piracetam improves activated blood flow and facilitates rehabilitation of poststroke aphasic patients. Stroke 2000; 31: 2112-2116
• 75 Enderby P, Broeckx J, Hospers W. et al. Effect of piracetam on recovery and rehabilitation after stroke: A double blind, placebo-controlled study. Clin Neuropharmacol 1994; 17: 320-331
• 76 Greener J, Enderby P, Whurr R. Pharmacological treatment for aphasia following stroke. Editorial Group: Cochrane Stroke Group. Published Online: 12 MAY 2010. Assessed as up-to-date: 4 JUL 2001. DOI:10.1002/14651858.CD000424
• 77 Güngör L, Terzi M, Onar MK. et al. Does long term use of piracetam improve speech disturbances due to ischemic cerebrovascular diseases?. Brain Lang 2011; 117: 23-27
• 78 Orgogozo JM. Piracetam in the treatment of acute stroke. Pharmacopsychiatry 1999; 32: 25-32
• 79 Kauhanen ML, Korpelainen JT, Hiltunen P. et al. Poststroke depression correlates with cognititve impairment and neurological deficits. Stroke 1999; 30: 1875-1880
• 80 Aström M, Adolfsson R, Asplund K. Major depression in stroke patients. A 3-year longitudinal study. Stroke 1993; 24: 976-982
• 81 Michael J, Reding MD, Louise A. et al Antidepressant therapy after stroke a double-blind trial. Arch Neurol 1986; 43: 763-765
• 82 Dam M, Tonin P, De Boni A. et al. Effects of fluoxetine and maprotiline on functional recovery in poststroke hemiplegic patients undergoing rehabilitation therapy. Stroke 1996; 27: 1211-1214
• 83 Narushima K, Chan K, Kosier J. et al. Does cognitive recovery aftertreatment of poststroke depression last? A 2-year follow-up of cognitive function associated with poststroke depression. Am J Psychiatry 2003; 160: 1157-1162
• 84 Jorge RE, Robinson RG, Arndt S. Mortality and poststroke depression: A placebo-controlled trial of antidepressants. Am J Psychiatry 2003; 160: 1823-1829
• 85 Chollet F, Tardy J, Albucher JF. et al. Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): A randomised placebo-controlled trial. Lancet Neurol 2011; 10: 123-130
• 86 Müller WE, Frankfurt aM. Normalisierung gestörter Neuroplastizitätsmechanismen als gemeinsame Endstrecke im Wirkungsmechanismus von Antidepressiva. Die besondere Rolle von Tianeptin. Psychopharmakotherapie 2016; 23: 230-238
• 87 Watanabe Y, Gould E, Daniels DC. et al. Tianeptine attenuates stress-induced morphological changes in the hippocampus. Eur J Pharmacol 1992; 222: 157-162
• 88 Joffe RT, Lippert GP, Gray TA. et al. Mood disorder and multiple sclerosis. Arch Neurol 1987; 44: 376-378
• 89 Fredrikson S, Cheng Q, Jiang GX. et al. Elevated suicide risk among patients with multiple sclerosis in Sweden. Neuroepidemiology 2003; 22: 146-152
• 90 Meythaler JM, Brunner RC, Johnson A. et al. Amantadine to improve neurorecovery in traumatic brain injury-associated diffuse axonal injury: a pilot double-blind randomized trial. J Head Trauma Rehabil 2002; 17: 300-313
• 91 Zafonte RD, Watanabe T, Mann NR. Amantadine: A potential treatment for the minimally conscious state. Brain Inj 1998; 12: 617-621
• 92 Zafonte RD, Lexell J, Cullen N. Possible applications for dopaminergic agents following traumatic brain injury: Part 2. J Head Trauma Rehabil 2001; 16: 112-116
• 93 Patrick PD, Buck ML, Conaway MR. et al. The use of dopamine enhancing medications with children in low response states following brain injury. Brain Inj 2003; 17: 497-506
• 94 Patrick PD, Blackman JA, Mabry JL. et al. Dopamine agonist therapy in low-response children following traumatic brain injury. J Child Neurol 2006; 21: 879-885
• 95 Krimchansky B, Keren O, Sazbon L. et al. Differential time and related appearance of signs, indicating improvement in the state of consciousness in vegetative state traumatic brain injury (VS-TBI) patients after initiation of dopamine treatment. Brain Inj 2004; 18: 1099-1105
• 96 Patrick PD, Blackman JA, Mabry JL. et al. Dopamine agonist therapy in low-response children following traumatic brain injury. J Child Neurol 2006; 21: 879-885
• 97 Passler MA, Riggs RV. Positive outcomes in traumatic brain injury-vegetative state: Patients treated with bromocriptine. Arch Phys Med Rehabil 2001; 82: 311-315
• 98 Fridman EA, Krimchansky BZ, Bonetto M. et al. Continuous subcutaneous apomorphine for severe disorders of consciousness after traumatic brain injury. Brain Inj 2010; 24: 636-641
• 99 Martin RT, Whyte J. The effects of methylphenidate on command following and yes/no communication in persons with severe disorders of consciousness: A meta-analysis of n-of-1 studies. Am J Phys Med Rehabil 2007; 86: 613-620
• 100 Meythaler JM, Depalma L, Devivo MJ. et al. Sertraline to improve arousal and alertness in severe traumatic brain injury secondary tomotor vehicle crashes. Brain Inj 2001; 15: 321-331
• 101 Reinhard DL, Whyte J, Sandel ME. Improved arousal and initiation following tricyclic antidepressant use in severe brain injury. Arch Phys Med Rehabil1996 77: 80-83
• 102 Teitelman E. Off-label uses of modafinil. Am J Psychiatry. 2001; 158: 1341
• 103 Jha A, Weintraub A, Allshouse A. et al. A randomized trial of modafinil for the treatment of fatigue and excessive daytime sleepiness in individuals with chronic traumatic brain injury. J Head Trauma Rehabil 2008; 23: 52-63
• 104 Cohen SI, Duong TT. Increased arousal in a patient with anoxic brain injury after administration of zolpidem. Am J Phys Med Rehabil 2008; 87: 229-231
• 105 Du B, Shan A, Zhang Y. et al. Zolpidem arouses patients in vegetative state after brain injury: quantitative evaluation and indications. Am J Med Sci 2014; 347: 178-182
• 106 Brefel-Courbon C, Payoux P, Ory F. et al. Clinical and imaging evidence of zolpidem effect in hypoxic encephalopathy. Ann Neurol 2007; 62: 102-105
• 107 Singh R, Mc Donald C, Dawson K. et al. Zolpidem in a minimally conscious state. Brain Injury 2007; 22 (01) 103-106
• 108 Thonnard M, Gosseries O, Demertzi A. et al. Effect of zolpidem in chronic disorders of consciousness: A prospective open-label study. 2013. Funct Neurol 2013; 28: 259-264
• 109 White J, Rajan R, Rosenbaum A. et al. Zolpidem and restoration of consciousness. Am J Phys Med Rehabil 2014; 93: 101-113
• 110 Rammohan KW, Rosenberg JH, Lynn DJ. et al. Efficacy and safety of modafinil (Provigil®) for the treatment of fatigue in multiple sclerosis: A two-centre phase 2 study. J Neurol Neurosurg Psychiatry 2002; 72: 179-183
• 111 Stankoff B, Waubant E, Confavreux C. et al. Modafinil for fatigue in MS: A randomized placebo-controlled double-blind study. Neurology 2005; 64: 1139-1143
• 112 Weinshenker BG, Penman M, Bass B. et al. A double blind, randomized,crossover trial of pemoline in fatigue associated with multiple sclerosis. Neurology 1992; 42: 1468-1471
• 113 Krupp LB, Coyle PK, Doscher C. et al. Fatigue therapy in multiple sclerosis: Results of a double blind, randomized, parallel trial of amantadine, pemoline, and placebo. Neurology 1995; 45: 1956-1961
• 114 Murray TJ. Amantadine therapy for fatigue in multiple sclerosis. Can J Neurol Sci 1985; 12: 251-254
• 115 Canadian MS Research Group. A randomized controlled trial of amantadine in fatigue associated with MS. Can J Neurosci 1987; 14: 273-279
• 116 Cohen RA, Fisher M. Amantadine treatment of fatigue associated with multiplesclerosis. Arch Neurol 1989; 46: 676-680
• 117 Asano M, Finlayson ML. Meta-analysis of three different types of fatigue management interventions for people with multiple sclerosis: exercise, education and medication. Mult Scler Int 2014; 1-12
• 118 Achiron A, Givon U, Magalashvili D. et al. Effect of Alfacalcidol on multiple sclerosis-related fatigue: A randomized, double-blind placebo-controlled study. Mult Scler 2015; 21: 767-775
• 119 Veauthier C, Paul F. Therapie der Fatigue bei Multipler Sklerose. Ein Behandlungsalgorithmus. Nervenarzt 2016; 87: 1310-1321
• 120 Kaur H, Prakash A, Meghi B. Drug therapy in stroke: From preclinical to clinical studies. Pharmacology 2013; 92: 324-334
• 121 Xu SY, Pan SY. The failure of animal models of neuroprotection in acute ischemic stroke to translate to clinical efficacy. Med Sci Monit Basic Res 2013; 19: 37-45
• 122 Tymianski M. Novel approaches to neuroprotection trials in acute ischemic stroke. Stroke 2013; 44: 2942-2950
• 123 Rogalewski A, Schneider A, Ringelstein EB. et al. Toward a multimodal neuroprotective treatment of stroke. Stroke 2006; 37: 1129-1136
• 124 Muresanu D, Heiss W, Hoemberg V. et al. Cerebrolysin and recovery after stroke (CARS). Stroke 2016; 47: 151-159
• 125 Heiss WD, Brainin M, Bornstein NM. et al. Cerebrolysin Acute Stroke Treatment in Asia (CASTA) Investigators et al. Cerebrolysin in patients with acute ischemic stroke in Asia: Results of a double-blind, placebo-controlled randomized trial. Stroke 2012; 43: 630-636
• 126 Chang WH, Park C-h, Kim DY. et al. Cerebrolysin combined with rehabilitation promotes motor recovery in patients with severe motor impairment after stroke. BMC Neurology 2016; 16: 31
• 127 Dilg P. Theriaca- die Königin der Arzneien – Deutsche Apothekerzeitung. 1986; 126: 2677-2682