Download PDF
Arquivos Brasileiros de Neurocirurgia: Brazilian Neurosurgery 2015; 34(03): 208-214
DOI: 10.1055/s-0035-1559890
Review Article | Artigo de Revisão
Thieme Publicações Ltda Rio de Janeiro, Brazil

Farmacoterapia no traumatismo craniano. Onde estamos? Para onde vamos? Porém, quando vamos?

Pharmacotherapy in Traumatic Brain Injury. Where we are? Where we are going? However, when?
Mariana Schumacher Welling
1   Acadêmica; Medicina da Universidade Estadual de Ponta Grossa (UEPG), Ponta Grossa, PR, Brasil
,
Leonardo C. Welling
2   Neurocirurgião; Professor Adjunto de Neurocirurgia da UEPG, Ponta Grossa, PR, Brasil
,
Eberval Gadelha Figueiredo
3   Neurocirurgião; Professor Assistente da Universidade de São Paulo (USP), São Paulo, SP, Brasil
› Author Affiliations
Further Information

Publication History

07 July 2014

12 June 2015

Publication Date:
10 August 2015 (online)

Also available at
   Permissions and Reprints

Resumo

O traumatismo cranioencefálico (TCE) apresenta aumento de sua prevalência e é um desafio para a sociedade atual. Lesões primárias são aquelas que ocorrem no momento do impacto. Lesões secundárias são as que ocorrem após a lesão inicial como uma resposta fisiológica/patológica. Isso causa uma cascata de eventos que pode durar um longo período. Enquanto as lesões primárias são irreverssíveis, as secundárias são potencialmente evitáveis se forem submetidas a triagem e estabilização adequadas, assim como ao correto manejo da oxigenação cerebral e controle da hipertensão intracraniana e pressão de perfusão cerebral. Devemos considerar o traumatismo craniano como um evento dinâmico com inúmeras janelas terapêuticas possíveis. Nesse contexto o desenvolvimento de agentes farmacológicos no tratamento do TCE é urgente. Na presente revisão os autores descrevem os principais fármacos que estão sendo estudados nos pacientes com traumatismo craniano. Concluímos que, apesar de investimentos substanciais em estudos de fase I e II, ainda há muitas lacunas no conhecimento, portanto esforços são necessários para que haja uma translação mais rápida para estudos de fase III.

Abstract

Traumatic brain injury (TBI) is an increasingly prevalent and complex challenge for society. Primary injuries are defined as those that occur at the moment of impact. Secondary injuries are those that occur after the initial injury as a consequence of physiologic / pathologic response to injury. This triggers a cascade of pathophysiological events that can extend over a long period of time. Whereas the primary injuries are considered irreversible, secondary injuries are potentially preventable with efficient triage and stabilization, management of parameters such as brain oxygenation, intracranial pressure, and cerebral perfusion pressure. Indeed, TBI should be thought of not as a static event, but rather a progressive injury with varying therapeutic windows. In this context the development of pharmacological treatment of patients with traumatic brain injury is urgent. In this review the authors describe the main drugs that are being studied in TBI patients. We conclude, despite substantial and ongoing investments in both phase I and II studies, there remain significant gaps in knowledge and faster translation to phase III clinical studies is mandatory.

Palavras-Chave

Traumatismo Craniano - Reabilitação - Farmacoterapia

Keywords

Traumatic Brain Injury - Rehabilitation - Pharmacotherapy
 

  • Referências

  • 1 Bales JW, Wagner AK, Kline AE, Dixon CE. Persistent cognitive dysfunction after traumatic brain injury: A dopamine hypothesis. Neurosci Biobehav Rev 2009; 33 (7) 981-1003
    CrossrefPubMedGoogle Scholar
  • 2 Gianutsos G, Chute S, Dunn JP. Pharmacological changes in dopaminergic systems induced by long-term administration of amantadine. Eur J Pharmacol 1985; 110 (3) 357-361
    CrossrefPubMedGoogle Scholar
  • 3 Dixon CE, Kraus MF, Kline AE , et al. Amantadine improves water maze performance without affecting motor behavior following traumatic brain injury in rats. Restor Neurol Neurosci 1999; 14 (4) 285-294
    PubMedGoogle Scholar
  • 4 Meythaler JM, Brunner RC, Johnson A, Novack TA. Amantadine to improve neurorecovery in traumatic brain injury-associated diffuse axonal injury: a pilot double-blind randomized trial. J Head Trauma Rehabil 2002; 17 (4) 300-313
    CrossrefPubMedGoogle Scholar
  • 5 Schneider WN, Drew-Cates J, Wong TM, Dombovy ML. Cognitive and behavioural efficacy of amantadine in acute traumatic brain injury: an initial double-blind placebo-controlled study. Brain Inj 1999; 13 (11) 863-872
    CrossrefPubMedGoogle Scholar
  • 6 Whyte J, Katz D, Long D , et al. Predictors of outcome in prolonged posttraumatic disorders of consciousness and assessment of medication effects: A multicenter study. Arch Phys Med Rehabil 2005; 86 (3) 453-462
    CrossrefPubMedGoogle Scholar
  • 7 Ballesteros J, Güemes I, Ibarra N, Quemada JI. The effectiveness of donepezil for cognitive rehabilitation after traumatic brain injury: a systematic review. J Head Trauma Rehabil 2008; 23 (3) 171-180
    CrossrefPubMedGoogle Scholar
  • 8 Blount PJ, Nguyen CD, McDeavitt JT. Clinical use of cholinomimetic agents: a review. J Head Trauma Rehabil 2002; 17 (4) 314-321
    CrossrefPubMedGoogle Scholar
  • 9 Bourgeois JA, Bahadur N, Minjares S. Donepezil for cognitive deficits following traumatic brain injury: a case report. J Neuropsychiatry Clin Neurosci 2002; 14 (4) 463-464
    CrossrefPubMedGoogle Scholar
  • 10 Foster M, Spiegel DR. Use of donepezil in the treatment of cognitive impairments of moderate traumatic brain injury. J Neuropsychiatry Clin Neurosci 2008; 20 (1) 106
    CrossrefPubMedGoogle Scholar
  • 11 Fujiki M, Kubo T, Kamida T , et al. Neuroprotective and antiamnesic effect of donepezil, a nicotinic acetylcholine-receptor activator, on rats with concussive mild traumatic brain injury. J Clin Neurosci 2008; 15 (7) 791-796
    CrossrefPubMedGoogle Scholar
  • 12 Fujiki M, Hikawa T, Abe T, Ishii K, Kobayashi H. Reduced short latency afferent inhibition in diffuse axonal injury patients with memory impairment. Neurosci Lett 2006; 405 (3) 226-230
    CrossrefPubMedGoogle Scholar
  • 13 Chen Y, Shohami E, Constantini S, Weinstock M. Rivastigmine, a brain-selective acetylcholinesterase inhibitor, ameliorates cognitive and motor deficits induced by closed-head injury in the mouse. J Neurotrauma 1998; 15 (4) 231-237
    CrossrefPubMedGoogle Scholar
  • 14 Silver JM, Koumaras B, Chen M , et al. Effects of rivastigmine on cognitive function in patients with traumatic brain injury. Neurology 2006; 67 (5) 748-755
    CrossrefPubMedGoogle Scholar
  • 15 Silver JM, Koumaras B, Meng X , et al. Long-term effects of rivastigmine capsules in patients with traumatic brain injury. Brain Inj 2009; 23 (2) 123-132
    CrossrefPubMedGoogle Scholar
  • 16 Diaz-Arrastia R, Kochanek PM, Bergold P , et al. Pharmacotherapy of traumatic brain injury: state of the science and the road forward: report of the Department of Defense Neurotrauma Pharmacology Workgroup. J Neurotrauma 2014; 31 (2) 135-158
    CrossrefPubMedGoogle Scholar
  • 17 Cognitive Remediation after Trauma Exposure: CREATE trial. NCT01416948. Disponível em: https://clinicaltrials.gov/ct2/show/NCT01416948
    PubMedGoogle Scholar
  • 18 Zhang HY, Yan H, Tang XC. Non-cholinergic effects of huperzine A: beyond inhibition of acetylcholinesterase. Cell Mol Neurobiol 2008; 28 (2) 173-183
    CrossrefPubMedGoogle Scholar
  • 19 Wang Y, Tang XC, Zhang HY. Huperzine A alleviates synaptic deficits and modulates amyloidogenic and nonamyloidogenic pathways in APPswe/PS1dE9 transgenic mice. J Neurosci Res 2012; 90 (2) 508-517
    CrossrefPubMedGoogle Scholar
  • 20 Fan Y, Hu J, Li J , et al. Effect of acidic oligosaccharide sugar chain on scopolamine-induced memory impairment in rats and its related mechanisms. Neurosci Lett 2005; 374 (3) 222-226
    CrossrefPubMedGoogle Scholar
  • 21 Li J, Wu HM, Zhou RL, Liu GJ, Dong BR. Huperzine A for Alzheimer's disease. Cochrane Database Syst Rev 2008; (2) CD005592
    PubMedGoogle Scholar
  • 22 Brustovetsky N, Dubinsky JM. Limitations of cyclosporin A inhibition of the permeability transition in CNS mitochondria. J Neurosci 2000; 20 (22) 8229-8237
    PubMedGoogle Scholar
  • 23 Sharov VG, Todor A, Khanal S, Imai M, Sabbah HN. Cyclosporine A attenuates mitochondrial permeability transition and improves mitochondrial respiratory function in cardiomyocytes isolated from dogs with heart failure. J Mol Cell Cardiol 2007; 42 (1) 150-158
    CrossrefPubMedGoogle Scholar
  • 24 Alessandri B, Rice AC, Levasseur J, DeFord M, Hamm RJ, Bullock MR. Cyclosporin A improves brain tissue oxygen consumption and learning/memory performance after lateral fluid percussion injury in rats. J Neurotrauma 2002; 19 (7) 829-841
    CrossrefPubMedGoogle Scholar
  • 25 Saganová K, Gálik J, Blaško J, Korimová A, Račeková E, Vanický I. Immunosuppressant FK506: focusing on neuroprotective effects following brain and spinal cord injury. Life Sci 2012; 91 (3-4) 77-82
    CrossrefPubMedGoogle Scholar
  • 26 Setkowicz Z, Guzik R. Injections of vehicle, but not cyclosporin A or tacrolimus (FK506), afford neuroprotection following injury in the developing rat brain. Acta Neurobiol Exp (Warsz) 2007; 67 (4) 399-409
    PubMedGoogle Scholar
  • 27 Sullivan PG, Rabchevsky AG, Hicks RR, Gibson TR, Fletcher-Turner A, Scheff SW. Dose-response curve and optimal dosing regimen of cyclosporin A after traumatic brain injury in rats. Neuroscience 2000; 101 (2) 289-295
    CrossrefPubMedGoogle Scholar
  • 28 Empey PE, McNamara PJ, Young B, Rosbolt MB, Hatton J. Cyclosporin A disposition following acute traumatic brain injury. J Neurotrauma 2006; 23 (1) 109-116
    CrossrefPubMedGoogle Scholar
  • 29 Mazzeo AT, Kunene NK, Gilman CB, Hamm RJ, Hafez N, Bullock MR. Severe human traumatic brain injury, but not cyclosporin a treatment, depresses activated T lymphocytes early after injury. J Neurotrauma 2006; 23 (6) 962-975
    CrossrefPubMedGoogle Scholar
  • 30 Hatton J, Rosbolt B, Empey P, Kryscio R, Young B. Dosing and safety of cyclosporine in patients with severe brain injury. J Neurosurg 2008; 109 (4) 699-707
    CrossrefPubMedGoogle Scholar
  • 31 Aminmansour B, Fard SA, Habibabadi MR, Moein P, Norouzi R, Naderan M. The efficacy of Cyclosporine-A on Diffuse Axonal Injury after Traumatic Brain Injury. Adv Biomed Res 2014; 3 (3) 35
    CrossrefPubMedGoogle Scholar
  • 32 Simard JM, Woo SK, Schwartzbauer GT, Gerzanich V. Sulfonylurea receptor 1 in central nervous system injury: a focused review. J Cereb Blood Flow Metab 2012; 32 (9) 1699-1717
    CrossrefPubMedGoogle Scholar
  • 33 Patel AD, Gerzanich V, Geng Z, Simard JM. Glibenclamide reduces hippocampal injury and preserves rapid spatial learning in a model of traumatic brain injury. J Neuropathol Exp Neurol 2010; 69 (12) 1177-1190
    CrossrefPubMedGoogle Scholar
  • 34 Benvenga S, Campenní A, Ruggeri RM, Trimarchi F. Clinical review 113: Hypopituitarism secondary to head trauma. J Clin Endocrinol Metab 2000; 85 (4) 1353-1361
    CrossrefPubMedGoogle Scholar
  • 35 Thum T, Hoeber S, Froese S , et al. Age-dependent impairment of endothelial progenitor cells is corrected by growth-hormone-mediated increase of insulin-like growth-factor-1. Circ Res 2007; 100 (3) 434-443
    CrossrefPubMedGoogle Scholar
  • 36 Devesa J, Reimunde P, Devesa P, Barberá M, Arce V. Growth hormone (GH) and brain trauma. Horm Behav 2013; 63 (2) 331-344
    CrossrefPubMedGoogle Scholar
  • 37 Takala J, Ruokonen E, Webster NR , et al. Increased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med 1999; 341 (11) 785-792
    CrossrefPubMedGoogle Scholar
  • 38 Yu F, Wang Z, Tchantchou F, Chiu CT, Zhang Y, Chuang DM. Lithium ameliorates neurodegeneration, suppresses neuroinflammation, and improves behavioral performance in a mouse model of traumatic brain injury. J Neurotrauma 2012; 29 (2) 362-374
    CrossrefPubMedGoogle Scholar
  • 39 Zhu ZF, Wang QG, Han BJ, William CP. Neuroprotective effect and cognitive outcome of chronic lithium on traumatic brain injury in mice. Brain Res Bull 2010; 83 (5) 272-277
    CrossrefPubMedGoogle Scholar
  • 40 Moeller SJ, Honorio J, Tomasi D , et al. Methylphenidate enhances executive function and optimizes prefrontal function in both health and cocaine addiction. Cereb Cortex 2014; 24 (3) 643-653
    CrossrefPubMedGoogle Scholar
  • 41 Wagner AK, Drewencki LL, Chen X , et al. Chronic methylphenidate treatment enhances striatal dopamine neurotransmission after experimental traumatic brain injury. J Neurochem 2009; 108 (4) 986-997
    CrossrefPubMedGoogle Scholar
  • 42 Moein H, Khalili HA, Keramatian K. Effect of methylphenidate on ICU and hospital length of stay in patients with severe and moderate traumatic brain injury. Clin Neurol Neurosurg 2006; 108 (6) 539-542
    CrossrefPubMedGoogle Scholar
  • 43 Kim HS, Suh YH. Minocycline and neurodegenerative diseases. Behav Brain Res 2009; 196 (2) 168-179
    CrossrefPubMedGoogle Scholar
  • 44 Bye N, Habgood MD, Callaway JK , et al. Transient neuroprotection by minocycline following traumatic brain injury is associated with attenuated microglial activation but no changes in cell apoptosis or neutrophil infiltration. Exp Neurol 2007; 204 (1) 220-233
    CrossrefPubMedGoogle Scholar
  • 45 Kovesdi E, Kamnaksh A, Wingo D , et al. Acute minocycline treatment mitigates the symptoms of mild blast-induced traumatic brain injury. Front Neurol 2012; 3: 111
    CrossrefPubMedGoogle Scholar
  • 46 Dodd S, Dean O, Copolov DL, Malhi GS, Berk M. N-acetylcysteine for antioxidant therapy: pharmacology and clinical utility. Expert Opin Biol Ther 2008; 8 (12) 1955-1962
    CrossrefPubMedGoogle Scholar
  • 47 Olive MF, Cleva RM, Kalivas PW, Malcolm RJ. Glutamatergic medications for the treatment of drug and behavioral addictions. Pharmacol Biochem Behav 2012; 100 (4) 801-810
    CrossrefPubMedGoogle Scholar
  • 48 Yi JH, Hazell AS. N-acetylcysteine attenuates early induction of heme oxygenase-1 following traumatic brain injury. Brain Res 2005; 1033 (1) 13-19
    CrossrefPubMedGoogle Scholar
  • 49 Hoffer ME, Balaban C, Slade MD, Tsao JW, Hoffer B. Amelioration of acute sequelae of blast induced mild traumatic brain injury by N-acetyl cysteine: a double-blind, placebo controlled study. PLoS ONE 2013; 8 (1) e54163
    CrossrefPubMedGoogle Scholar
  • 50 Liu L, Wang J, Zhao L , et al. Progesterone increases rat neural progenitor cell cycle gene expression and proliferation via extracellularly regulated kinase and progesterone receptor membrane components 1 and 2. Endocrinology 2009; 150 (7) 3186-3196
    CrossrefPubMedGoogle Scholar
  • 51 Sayeed I, Parvez S, Wali B, Siemen D, Stein DG. Direct inhibition of the mitochondrial permeability transition pore: a possible mechanism for better neuroprotective effects of allopregnanolone over progesterone. Brain Res 2009; 1263: 165-173
    CrossrefPubMedGoogle Scholar
  • 52 Hua F, Reiss JI, Tang H , et al. Progesterone and low-dose vitamin D hormone treatment enhances sparing of memory following traumatic brain injury. Horm Behav 2012; 61 (4) 642-651
    CrossrefPubMedGoogle Scholar
  • 53 Cutler SM, Cekic M, Miller DM, Wali B, VanLandingham JW, Stein DG. Progesterone improves acute recovery after traumatic brain injury in the aged rat. J Neurotrauma 2007; 24 (9) 1475-1486
    CrossrefPubMedGoogle Scholar
  • 54 Djebaili M, Hoffman SW, Stein DG. Allopregnanolone and progesterone decrease cell death and cognitive deficits after a contusion of the rat pre-frontal cortex. Neuroscience 2004; 123 (2) 349-359
    CrossrefPubMedGoogle Scholar
  • 55 Béziaud T, Ru Chen X, El Shafey N , et al. Simvastatin in traumatic brain injury: effect on brain edema mechanisms. Crit Care Med 2011; 39 (10) 2300-2307
    CrossrefPubMedGoogle Scholar
  • 56 Wang H, Lynch JR, Song P , et al. Simvastatin and atorvastatin improve behavioral outcome, reduce hippocampal degeneration, and improve cerebral blood flow after experimental traumatic brain injury. Exp Neurol 2007; 206 (1) 59-69
    CrossrefPubMedGoogle Scholar
  • 57 Lu D, Qu C, Goussev A , et al. Statins increase neurogenesis in the dentate gyrus, reduce delayed neuronal death in the hippocampal CA3 region, and improve spatial learning in rat after traumatic brain injury. J Neurotrauma 2007; 24 (7) 1132-1146
    CrossrefPubMedGoogle Scholar
  • 58 Sierra S, Ramos MC, Molina P, Esteo C, Vázquez JA, Burgos JS. Statins as neuroprotectants: a comparative in vitro study of lipophilicity, blood-brain-barrier penetration, lowering of brain cholesterol, and decrease of neuron cell death. J Alzheimers Dis 2011; 23 (2) 307-318
    PubMedGoogle Scholar