Skip to main content

Advertisement

SpringerLink
Log in

The High Cost of Stroke and Stroke Cytoprotection Research

  • Opinion Paper
  • Published:
Translational Stroke Research Aims and scope Submit manuscript

Abstract

Acute ischemic stroke is inadequately treated in the USA and worldwide due to a lengthy history of neuroprotective drug failures in clinical trials. The majority of victims must endure life-long disabilities that not only affect their livelihood, but also have an enormous societal economic impact. The rapid development of a neuroprotective or cytoprotective compound would allow future stroke victims to receive a treatment to reduce disabilities and further promote recovery of function. This opinion article reviews in detail the enormous costs associated with developing a small molecule to treat stroke, as well as providing a timely overview of the cell-death time-course and relationship to the ischemic cascade. Distinct temporal patterns of cell-death of neurovascular unit components provide opportunities to intervene and optimize new cytoprotective strategies. However, adequate research funding is mandatory to allow stroke researchers to develop and test their novel therapeutic approach to treat stroke victims.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Poirier J, Derouesné D. VIII.9: Apoplexy and Stroke The Cambridge World History of Human Disease1993. p. 10.1017/CHOL9780521332866.071.

  2. Wepfer J. Observationes anatomicae ex cadaveribus eorum quos sustulit apoplexia (cum exercitatione de eious loco affecto). Schaffussii: J C Suteri. 1658:670.

  3. Gurdjian ES, Gurdjian ES. History of occlusive cerebrovascular disease I. From Wepfer to Moniz. Arch Neurol. 1979;36(6):340–3.

    Article  CAS  PubMed  Google Scholar 

  4. Willis T. Cerebri Anatome: cui accessit nervorum descriptio et usus. London; 1664.

  5. Virchow R. Thrombose und Embolie: Gefässenzýndung und Septische Infektion, in Gesammelte Abhandlungen zur wissen schaftlichen Medicin: Frankfurt, a. M., Meidinger, Sohn und Co, 1856.

  6. Dechambre A. Dictionnaire Encyclopédique des Sciences Médicales. Paris; 1866.

  7. Bramwell B. Spontaneous meningeal haemorrhage. Edinburgh Medical Journal. 1886;32:101.

    Google Scholar 

  8. Symonds CP. Spontaneous sub-arachnoid haemorrhage. Proceedings of the Royal Society of Medicine. Neurol Sect. 1924;17:39–52.

    Google Scholar 

  9. Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K, et al. Heart disease and stroke statistics—2009 update: a report from the American Heart Association statistics committee and stroke statistics subcommittee. Circulation. 2009;119(3):480–6.

    Article  PubMed  Google Scholar 

  10. Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, et al. Executive summary: heart disease and stroke statistics—2010 update: a report from the American Heart Association. Circulation. 2010;121(7):948–54.

    Article  PubMed  Google Scholar 

  11. Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, et al. Heart disease and stroke statistics—2010 update: a report from the American Heart Association. Circulation. 2010;121(7):e46–e215.

    Article  PubMed  Google Scholar 

  12. Lapchak PA. Hemorrhagic transformation following ischemic stroke: significance, causes, and relationship to therapy and treatment. Curr Neurol Neurosci Rep. 2002;2(1):38–43.

    Article  PubMed  Google Scholar 

  13. Lyden PD, Zivin JA. Hemorrhagic transformation after cerebral ischemia: mechanisms and incidence. Cerebrovasc Brain Metab Rev. 1993;5(1):1–16.

    CAS  PubMed  Google Scholar 

  14. Bernstein RA, Del-Signore M. Recent advances in the management of acute intracerebral hemorrhage. Curr Neurol Neurosci Rep. 2005;5(6):483–7.

    Article  PubMed  Google Scholar 

  15. van Gijn J, Kerr RS, Rinkel GJ. Subarachnoid haemorrhage. Lancet. 2007;369(9558):306–18.

    Article  PubMed  Google Scholar 

  16. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation. 2015;131(4):e29–322.

    Article  PubMed  Google Scholar 

  17. CDC. http://www.cdc.gov/Stroke/faqs.htm. 2016.

  18. Feigin VL, Forouzanfar MH, Krishnamurthi R, Mensah GA, Connor M, Bennett DA, et al. Global and regional burden of stroke during 1990–2010: findings from the global burden of disease study 2010. Lancet. 2014;383(9913):245–54.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Suwanwela NC, Poungvarin N. Asian stroke advisory P. Stroke burden and stroke care system in Asia. Neurol India. 2016;64(Suppl):S46–51.

    Article  PubMed  Google Scholar 

  20. Roth GA, Forouzanfar MH, Moran AE, Barber R, Nguyen G, Feigin VL, et al. Demographic and epidemiologic drivers of global cardiovascular mortality. N Engl J Med. 2015;372(14):1333–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. CLEAN M. http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1804.

  22. ESCAPE. https://clinicaltrials.gov/ct2/show/NCT01778335.

  23. REVASCAT. https://clinicaltrials.gov/ct2/show/NCT01692379.

  24. PRIME S. https://clinicaltrials.gov/ct2/show/NCT01657461.

  25. EXTEND-IA. https://clinicaltrials.gov/ct2/show/NCT01492725.

  26. THERAPY. https://clinicaltrials.gov/ct2/show/NCT01429350.

  27. THRACE. https://clinicaltrials.gov/ct2/show/NCT01062698.

  28. Bendszus M, Thomalla G, Hacke W, Knauth M, Gerloff C, Bonekamp S, et al. Early termination of THRILL, a prospective study of mechanical thrombectomy in patients with acute ischemic stroke ineligible for i.V. Thrombolysis. Clin Neuroradiol. 2016; doi:10.1007/s00062-016-0538-8.

    PubMed Central  Google Scholar 

  29. DAWN. https://www.clinicaltrialsgov/ct2/show/NCT02142283?term = DAWN&rank = 10.

  30. POSITIVE. https://www.clinicaltrialsgov/ct2/show/NCT01852201?term = nct01852201&rank = 1.

  31. Goyal M, Menon BK, van Zwam WH, Dippel DW, Mitchell PJ, Demchuk AM, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet. 2016;387(10029):1723–31.

    Article  PubMed  Google Scholar 

  32. Berkhemer OAFP, Beumer D, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372(1):11–20.

    Article  PubMed  CAS  Google Scholar 

  33. Goyal M, Demchuk AM, Menon BK, Eesa M, Rempel JL, Thornton J, et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015;372(11):1019–30.

    Article  CAS  PubMed  Google Scholar 

  34. Campbell BC, Mitchell PJ, Kleinig TJ, Dewey HM, Churilov L, Yassi N, et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med. 2015;372(11):1009–18.

    Article  CAS  PubMed  Google Scholar 

  35. Jovin TG, Chamorro A, Cobo E, de Miquel MA, Molina CA, Rovira A, et al. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med. 2015;372(24):2296–306.

    Article  CAS  PubMed  Google Scholar 

  36. Saver JL, Goyal M, Bonafe A, Diener HC, Levy EI, Pereira VM, et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med. 2015;372(24):2285–95.

    Article  CAS  PubMed  Google Scholar 

  37. Rebello LC, Haussen DC, Grossberg JA, Belagaje S, Lima A, Anderson A, et al. Early endovascular treatment in intravenous tissue plasminogen activator-ineligible patients. Stroke. 2016;47(4):1131–4.

    Article  CAS  PubMed  Google Scholar 

  38. Powers WJ, Derdeyn CP, Biller J, Coffey CS, Hoh BL, Jauch EC, et al. 2015 American Heart Association/American Stroke Association focused update of the 2013 guidelines for the early Management of Patients with Acute Ischemic Stroke Regarding Endovascular Treatment: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2015;46(10):3020–35.

    Article  CAS  PubMed  Google Scholar 

  39. Xie X, Lambrinos A, Chan B, Dhalla IA, Krings T, Casaubon LK, et al. Mechanical thrombectomy in patients with acute ischemic stroke: a cost-utility analysis. CMAJ Open. 2016;4(2):E316–25.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Aronsson M, Persson J, Blomstrand C, Wester P, Levin LA. Cost-effectiveness of endovascular thrombectomy in patients with acute ischemic stroke. Neurology. 2016;86(11):1053–9.

    Article  PubMed  Google Scholar 

  41. Mangla S, O'Connell K, Kumari D, Shahrzad M. Novel model of direct and indirect cost-benefit analysis of mechanical embolectomy over IV tPA for large vessel occlusions: a real-world dollar analysis based on improvements in mRS. J Neurointerv Surg. 2016; doi:10.1136/neurintsurg-2015-012152.

    PubMed  Google Scholar 

  42. Lobotesis K, Veltkamp R, Carpenter IH, Claxton LM, Saver JL, Hodgson R. Cost-effectiveness of stent-retriever thrombectomy in combination with IV t-PA compared with IV t-PA alone for acute ischemic stroke in the UK. J Med Econ. 2016;19(8):785–94.

    Article  PubMed  Google Scholar 

  43. Health Quality Ontario. Mechanical thrombectomy in patients with acute ischemic stroke: a health technology assessment. Ont Health Technol Assess Ser. 2016;16(4):1–79.

    Google Scholar 

  44. Ganesalingam J, Pizzo E, Morris S, Sunderland T, Ames D, Lobotesis K. Cost-utility analysis of mechanical thrombectomy using stent retrievers in acute ischemic stroke. Stroke. 2015;46(9):2591–8.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Zivin JA, Simmons J. tPA for stroke : the story of a controversial drug. New York: Oxford University Press; 2011. xiv, 191 p. p.

  46. Genentech. http://www.nytimes.com/1995/04/13/business/company-reports-genentech-earnings-exceed-expectations.html

  47. TNKase. https://www.scribd.com/document/9700876/Government-of-Canada-PMPRB-report-on-pricing-of-TNKase-tenecteplase

  48. Yamaguchi T, Mori E, Minematsu K, Nakagawara J, Hashi K, Saito I, et al. Alteplase at 0.6 mg/kg for acute ischemic stroke within 3 hours of onset: Japan alteplase clinical trial (J-ACT). Stroke. 2006;37(7):1810–5.

    Article  CAS  PubMed  Google Scholar 

  49. Lees KR, Bluhmki E, von Kummer R, Brott TG, Toni D, Grotta JC, et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet. 2010;375(9727):1695–703.

    Article  CAS  PubMed  Google Scholar 

  50. Bluhmki E, Chamorro A, Davalos A, Machnig T, Sauce C, Wahlgren N, et al. Stroke treatment with alteplase given 3.0-4.5 h after onset of acute ischaemic stroke (ECASS III): additional outcomes and subgroup analysis of a randomised controlled trial. Lancet Neurol. 2009;8(12):1095–102.

    Article  CAS  PubMed  Google Scholar 

  51. NINDS. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA stroke study group. N Engl J Med. 1995;333(24):1581–7.

    Article  Google Scholar 

  52. Hacke W, Kaste M, Bluhmki E, Brozman M, Davalos A, Guidetti D, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359(13):1317–29.

    Article  CAS  PubMed  Google Scholar 

  53. Lansberg MG, Bluhmki E, Thijs VN. Efficacy and safety of tissue plasminogen activator 3 to 4.5 hours after acute ischemic stroke: a metaanalysis. Stroke. 2009;40(7):2438–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Fang MC, Cutler DM, Rosen AB. Trends in thrombolytic use for ischemic stroke in the United States. J Hosp Med. 2010;5(7):406–9.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Reeves MJ, Arora S, Broderick JP, Frankel M, Heinrich JP, Hickenbottom S, et al. Acute stroke care in the US: results from 4 pilot prototypes of the Paul Coverdell National Acute Stroke Registry. Stroke. 2005;36(6):1232–40.

    Article  PubMed  Google Scholar 

  56. Schwamm LH, Ali SF, Reeves MJ, Smith EE, Saver JL, Messe S, et al. Temporal trends in patient characteristics and treatment with intravenous thrombolysis among acute ischemic stroke patients at get with the guidelines-stroke hospitals. Circ Cardiovasc Qual Outcomes. 2013;6(5):543–9.

    Article  PubMed  Google Scholar 

  57. Joo H, Wang G, George MG. Use of intravenous tissue plasminogen activator and hospital costs for patients with acute ischaemic stroke aged 18-64 years in the USA. Stroke Vasc Neurol. 2016;1(1):8–15.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Arora R, Salamon E, Katz JM, Cox M, Saver JL, Bhatt DL, et al. Use and outcomes of intravenous thrombolysis for acute ischemic stroke in patients >/=90 Years of age. Stroke. 2016;47(9):2347–54.

    Article  CAS  PubMed  Google Scholar 

  59. Taylor TN. The medical economics of stroke. Drugs. 1997;54(Suppl 3):51–7. discussion 7-8

    Article  PubMed  Google Scholar 

  60. Taylor TN, Davis PH, Torner JC, Holmes J, Meyer JW, Jacobson MF. Lifetime cost of stroke in the United States. Stroke. 1996;27(9):1459–66.

    Article  CAS  PubMed  Google Scholar 

  61. Boudreau DM, Guzauskas G, Villa KF, Fagan SC, Veenstra DL. A model of cost-effectiveness of tissue plasminogen activator in patient subgroups 3 to 4.5 hours after onset of acute ischemic stroke. Ann Emerg Med. 2013;61(1):46–55.

    Article  PubMed  Google Scholar 

  62. Boudreau DM, Guzauskas GF, Chen E, Lalla D, Tayama D, Fagan SC, et al. Cost-effectiveness of recombinant tissue-type plasminogen activator within 3 hours of acute ischemic stroke: current evidence. Stroke. 2014;45(10):3032–9.

    Article  PubMed  Google Scholar 

  63. Henninger N, Fisher M. Extending the time window for endovascular and pharmacological reperfusion. Transl Stroke Res. 2016;7(4):284–93.

    Article  CAS  PubMed  Google Scholar 

  64. Cassidy JM, Cramer SC. Spontaneous and therapeutic-induced mechanisms of functional recovery after stroke. Transl Stroke Res. 2016; doi:10.1007/s12975-016-0467-5.

    PubMed  Google Scholar 

  65. Linfante I, Cipolla MJ. Improving reperfusion therapies in the era of mechanical thrombectomy. Transl Stroke Res. 2016;7(4):294–302.

    Article  PubMed  Google Scholar 

  66. Lyden P, Weymer S, Coffey C, Cudkowicz M, Berg S, O'Brien S, et al. Selecting patients for intra-arterial therapy in the context of a clinical trial for neuroprotection. Stroke. 2016;47(12):2979–85. doi:10.1161/STROKEAHA.116.013881.

    Article  CAS  PubMed  Google Scholar 

  67. Lapchak PA. Critical early Thrombolytic & Endovascular Reperfusion Therapy for Acute Ischemic Stroke Victims: a call for adjunct neuroprotection. Translational Stroke Research. 2015;6(5):345–54. doi:10.1007/s12975-015-0419-5(6):345-54.

  68. Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke. 1999; 30(12):2752–8.

  69. Landis SC, Amara SG, Asadullah K, Austin CP, Blumenstein R, Bradley EW, et al. A call for transparent reporting to optimize the predictive value of preclinical research. Nature. 2012;490(7419):187–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Lapchak PA. Scientific rigor recommendations for optimizing the clinical applicability of translational research. J Neurol Neurophysiol. 2012;3:e111.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Lapchak PA. Recommendations and practices to optimize stroke therapy: developing effective translational research programs. Stroke. 2013;44(3):841–3.

    Article  PubMed  Google Scholar 

  72. Crossley NA, Sena E, Goehler J, Horn J, van der Worp B, Bath PM, et al. Empirical evidence of bias in the design of experimental stroke studies: a metaepidemiologic approach. Stroke. 2008;39(3):929–34.

    Article  PubMed  Google Scholar 

  73. Hirst JA, Howick J, Aronson JK, Roberts N, Perera R, Koshiaris C, et al. The need for randomization in animal trials: an overview of systematic reviews. PLoS One. 2014;9(6):e98856.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Saver JL. Time is brain—quantified. Stroke. 2006;37(1):263–6.

    Article  PubMed  Google Scholar 

  75. Saver JL, Smith EE, Fonarow GC, Reeves MJ, Zhao X, Olson DM, et al. The "golden hour" and acute brain ischemia: presenting features and lytic therapy in >30,000 patients arriving within 60 minutes of stroke onset. Stroke. 2010;41(7):1431–9.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Lapchak PA. Fast neuroprotection (fast-NPRX) for acute ischemic stroke victims: the time for treatment is now. Transl Stroke Res. 2013;4(6):704–9.

    Article  PubMed  Google Scholar 

  77. Desai JA, Smith EE. Prenotification and other factors involved in rapid tPA administration. Curr Atheroscler Rep. 2013;15(7):337.

    Article  PubMed  CAS  Google Scholar 

  78. Olson DM, Constable M, Britz GW, Lin CB, Zimmer LO, Schwamm LH, et al. A qualitative assessment of practices associated with shorter door-to-needle time for thrombolytic therapy in acute ischemic stroke. J Neurosci Nurs. 2011;43(6):329–36.

    Article  PubMed  Google Scholar 

  79. Fonarow GC, Smith EE, Saver JL, Reeves MJ, Hernandez AF, Peterson ED, et al. Improving door-to-needle times in acute ischemic stroke: the design and rationale for the American Heart Association/American Stroke Association's target: stroke initiative. Stroke. 2011;42(10):2983–9.

    Article  PubMed  Google Scholar 

  80. Mokin M, Snyder KV, Siddiqui AH, Levy EI, Hopkins LN. Recent endovascular stroke trials and their impact on stroke Systems of Care. J Am Coll Cardiol. 2016;67(22):2645–55.

    Article  PubMed  Google Scholar 

  81. Carmichael ST. The 3 Rs of stroke biology: radial, relayed, and regenerative. Neurotherapeutics. 2016;13(2):348–59.

    Article  CAS  PubMed  Google Scholar 

  82. Lapchak PA. Drug-like property profiling of novel neuroprotective compounds to treat acute ischemic stroke: guidelines to develop pleiotropic molecules. Transl Stroke Res. 2013;4(3):328–42.

    Article  CAS  PubMed  Google Scholar 

  83. Lipinski CA. Drug-like properties and the causes of poor solubility and poor permeability. J Pharmacol Toxicol Methods. 2000;44(1):235–49.

    Article  CAS  PubMed  Google Scholar 

  84. Lipinski CA. Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov Today Technol. 2004;1(4):337–41.

    Article  CAS  PubMed  Google Scholar 

  85. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001;46(1–3):3–26.

    Article  CAS  PubMed  Google Scholar 

  86. Hellinger E, Veszelka S, Toth AE, Walter F, Kittel A, Bakk ML, et al. Comparison of brain capillary endothelial cell-based and epithelial (MDCK-MDR1, Caco-2, and VB-Caco-2) cell-based surrogate blood-brain barrier penetration models. Eur J Pharm Biopharm. 2012;82(2):340–51.

    Article  CAS  PubMed  Google Scholar 

  87. Laine R. Metabolic stability: main enzymes involved and best tools to assess it. Curr Drug Metab. 2008;9(9):921–7.

    Article  CAS  PubMed  Google Scholar 

  88. Brimecombe JC, Kirsch GE, Brown AM. Test article concentrations in the hERG assay: losses through the perfusion, solubility and stability. J Pharmacol Toxicol Methods. 2009;59(1):29–34.

    Article  CAS  PubMed  Google Scholar 

  89. Cheng CS, Alderman D, Kwash J, Dessaint J, Patel R, Lescoe MK, et al. A high-throughput HERG potassium channel function assay: an old assay with a new look. Drug Dev Ind Pharm. 2002;28(2):177–91.

    Article  CAS  PubMed  Google Scholar 

  90. Gintant G. An evaluation of hERG current assay performance: translating preclinical safety studies to clinical QT prolongation. Pharmacol Ther. 2011;129(2):109–19.

    Article  CAS  PubMed  Google Scholar 

  91. Goineau S, Legrand C, Froget G. Whole-cell configuration of the patch-clamp technique in the hERG channel assay to predict the ability of a compound to prolong QT interval. Curr Protoc Pharmacol. 2012; Chapter 10:Unit 10 5.

  92. Yu HB, Zou BY, Wang XL, Li M. Investigation of miscellaneous hERG inhibition in large diverse compound collection using automated patch-clamp assay. Acta Pharmacol Sin. 2016;37(1):111–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. McDonnell AM, Dang CH. Basic review of the cytochrome p450 system. J Adv Pract Oncol. 2013;4(4):263–8.

    PubMed  PubMed Central  Google Scholar 

  94. Hedlund E, Gustafsson JA, Warner M. Cytochrome P450 in the brain: a review. Curr Drug Metab. 2001;2(3):245–63.

    Article  CAS  PubMed  Google Scholar 

  95. Evers R, Dallas S, Dickmann LJ, Fahmi OA, Kenny JR, Kraynov E, et al. Critical review of preclinical approaches to investigate cytochrome p450-mediated therapeutic protein drug-drug interactions and recommendations for best practices: a white paper. Drug Metab Dispos. 2013;41(9):1598–609.

    Article  CAS  PubMed  Google Scholar 

  96. Lapchak PA, Bombien R, Rajput PS. J-147 a Novel Hydrazide Lead Compound to Treat Neurodegeneration: CeeTox Safety and Genotoxicity Analysis. J Neurol Neurophysiol. 2013 ; 4(3).

  97. Lapchak PA, Schubert DR, Maher PA. Delayed treatment with a novel neurotrophic compound reduces behavioral deficits in rabbit ischemic stroke. J Neurochem. 2011;116(1):122–31.

    Article  CAS  PubMed  Google Scholar 

  98. Kirsch-Volders M, Decordier I, Elhajouji A, Plas G, Aardema MJ, Fenech M. In vitro genotoxicity testing using the micronucleus assay in cell lines, human lymphocytes and 3D human skin models. Mutagenesis. 2011;26(1):177–84.

    Article  CAS  PubMed  Google Scholar 

  99. Wiesner J, Ziemann C, Hintz M, Reichenberg A, Ortmann R, Schlitzer M, et al. FR-900098, an antimalarial development candidate that inhibits the non-mevalonate isoprenoid biosynthesis pathway, shows no evidence of acute toxicity and genotoxicity. Virulence. 2016;7(6):718–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Steinmetz KL, Spack EG. The basics of preclinical drug development for neurodegenerative disease indications. BMC Neurol. 2009;9(Suppl 1):S2.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Pellegatti M. Preclinical in vivo ADME studies in drug development: a critical review. Expert Opin Drug Metab Toxicol. 2012;8(2):161–72.

    Article  CAS  PubMed  Google Scholar 

  102. Fisher M. Recommendations for advancing development of acute stroke therapies: stroke therapy academic industry roundtable 3. Stroke. 2003;34(6):1539–46.

    Article  CAS  PubMed  Google Scholar 

  103. Fisher M, Hanley DF, Howard G, Jauch EC, Warach S. Recommendations from the STAIR V meeting on acute stroke trials, technology and outcomes. Stroke. 2007;38(2):245–8.

    Article  PubMed  Google Scholar 

  104. Saver JL, Albers GW, Dunn B, Johnston KC, Fisher M, Consortium SV. Stroke therapy academic industry roundtable (STAIR) recommendations for extended window acute stroke therapy trials. Stroke. 2009;40(7):2594–600.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Albers GW, Goldstein LB, Hess DC, Wechsler LR, Furie KL, Gorelick PB, et al. Stroke treatment academic industry roundtable (STAIR) recommendations for maximizing the use of intravenous thrombolytics and expanding treatment options with intra-arterial and neuroprotective therapies. Stroke. 2011;42(9):2645–50.

    Article  PubMed  Google Scholar 

  106. Ahnstedt H, McCullough LD, Cipolla MJ. The importance of considering sex differences in translational stroke research. Transl Stroke Res. 2016;7(4):261–73.

    Article  CAS  PubMed  Google Scholar 

  107. Ergul A, Hafez S, Fouda A, Fagan SC. Impact of comorbidities on acute injury and recovery in preclinical stroke research: focus on hypertension and diabetes. Transl Stroke Res. 2016;7(4):248–60.

    Article  CAS  PubMed  Google Scholar 

  108. King AJ. The use of animal models in diabetes research. Br J Pharmacol. 2012;166(3):877–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Sasase T, Ohta T, Masuyama T, Yokoi N, Kakehashi A, Shinohara M. The spontaneously diabetic torii rat: an animal model of nonobese type 2 diabetes with severe diabetic complications. J Diabetes Res. 2013;2013:976209.

    PubMed  PubMed Central  Google Scholar 

  110. Kemmochi Y, Fukui K, Maki M, Kimura S, Ishii Y, Sasase T, et al. Metabolic disorders and diabetic complications in spontaneously diabetic Torii Lepr (fa) rat: a new obese type 2 diabetic model. J Diabetes Res. 2013;2013:948257.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Hossmann KA. The two pathophysiologies of focal brain ischemia: implications for translational stroke research. J Cereb Blood Flow Metab. 2012;32(7):1310–6.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Lapchak PA. A clinically relevant rabbit embolic stroke model for acute ischemic stroke therapy development: mechanisms & targets. In: Lapchak PA, Zhang JH, editors.: Translational Stroke Research: From Target Selection to Clinical Trials, Springer, USA; 2011. Chapter 27, p. 541–84

  113. Lapchak PA. A cost-effective rabbit embolic stroke bioassay: insight into the development of acute ischemic stroke therapy. Transl Stroke Res. 2015;6(2):99–103.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Turner R, Jickling G. Sharp, F are underlying assumptions of current animal models of human stroke correct: from STAIRS to high hurdles? Translational Stroke Research. 2011;2(2):138–43.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Kent TA, Mandava P. Embracing biological and methodological variance in a new approach to pre-clinical stroke testing. Transl Stroke Res. 2016;7(4):274–83.

    Article  PubMed  Google Scholar 

  116. Lapchak PA, Chapman DF, Zivin JA. Metalloproteinase inhibition reduces thrombolytic (tissue plasminogen activator)-induced hemorrhage after thromboembolic stroke. Stroke. 2000;31(12):3034–40.

    Article  CAS  PubMed  Google Scholar 

  117. Liu DZ, Sharp FR. Excitatory and Mitogenic signaling in cell death, blood-brain barrier breakdown, and BBB repair after intracerebral hemorrhage. Transl Stroke Res. 2012;3(Suppl 1):62–9.

    Article  PubMed  Google Scholar 

  118. Turner RJ, Sharp FR. Implications of MMP9 for blood brain barrier disruption and hemorrhagic transformation following ischemic stroke. Front Cell Neurosci. 2016;10:56.

    Article  PubMed  PubMed Central  Google Scholar 

  119. Kassner A, Merali Z. Assessment of blood-brain barrier disruption in stroke. Stroke. 2015;46(11):3310–5.

    Article  PubMed  Google Scholar 

  120. Borlongan CV. The blood brain barrier in stroke. Curr Pharm Des. 2012;18(25):3613–4.

    Article  CAS  PubMed  Google Scholar 

  121. Demaerschalk BM. Alteplase treatment in acute stroke: incorporating Food and Drug Administration prescribing information into existing acute stroke management guide. Curr Atheroscler Rep. 2016;18(8):53.

    Article  PubMed  CAS  Google Scholar 

  122. Benz RD. Toxicological and clinical computational analysis and the US FDA/CDER. Expert Opin Drug Metab Toxicol. 2007;3(1):109–24.

    Article  CAS  PubMed  Google Scholar 

  123. Muller PY, Milton M, Lloyd P, Sims J, Brennan FR. The minimum anticipated biological effect level (MABEL) for selection of first human dose in clinical trials with monoclonal antibodies. Curr Opin Biotechnol. 2009;20(6):722–9.

    Article  CAS  PubMed  Google Scholar 

  124. Sharma V, McNeill JH. To scale or not to scale: the principles of dose extrapolation. Br J Pharmacol. 2009;157(6):907–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Lapchak PA, Araujo DM, Zivin JA. Comparison of tenecteplase with alteplase on clinical rating scores following small clot embolic strokes in rabbits. Exp Neurol. 2004;185(1):154–9.

    Article  CAS  PubMed  Google Scholar 

  126. Lapchak PA, Daley JT, Boitano PD. A blinded, randomized study of L-arginine in small clot embolized rabbits. Exp Neurol. 2015;266:143–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Meador V, Jordan W, Zimmermann J. Increasing throughput in lead optimization in vivo toxicity screens. Curr Opin Drug Discov Devel. 2002;5(1):72–8.

    CAS  PubMed  Google Scholar 

  128. Yoon M, Campbell JL, Andersen ME, Clewell HJ. Quantitative in vitro to in vivo extrapolation of cell-based toxicity assay results. Crit Rev Toxicol. 2012;42(8):633–52.

    Article  CAS  PubMed  Google Scholar 

  129. Lee SR, Wang X, Tsuji K, Lo EH. Extracellular proteolytic pathophysiology in the neurovascular unit after stroke. Neurol Res. 2004;26(8):854–61.

    Article  CAS  PubMed  Google Scholar 

  130. Richardson J, Murray D, House CK, Lowenkopf T. Successful implementation of the National Institutes of Health stroke scale on a stroke/neurovascular unit. J Neurosci Nurs. 2006;38(4 Suppl):309–15.

    Article  PubMed  Google Scholar 

  131. del Zoppo GJ. The neurovascular unit in the setting of stroke. J Intern Med. 2010;267(2):156–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Ago T. The neurovascular unit in health and ischemic stroke. Nihon Rinsho. 2016;74(4):583–8.

    PubMed  Google Scholar 

  133. Cai W, Zhang K, Li P, Zhu L, Xu J, Yang B, et al. Dysfunction of the neurovascular unit in ischemic stroke and neurodegenerative diseases: An aging effect. Ageing Res Rev 2016.

  134. ElAli A. The implication of neurovascular unit signaling in controlling the subtle balance between injury and repair following ischemic stroke. Neural Regen Res. 2016;11(6):914–5.

    PubMed  PubMed Central  Google Scholar 

  135. Lake EM, Bazzigaluppi P, Mester J, Thomason LA, Janik R, Brown M, et al. Neurovascular unit remodelling in the subacute stage of stroke recovery. Neuroimage. 2016. S1053-8119(16)30480-3. doi:10.1016/j.neuroimage.2016.09.016.

  136. Hermann DM, Buga AM, Popa-Wagner A. Neurovascular remodeling in the aged ischemic brain. J Neural Transm (Vienna). 2015;122(Suppl 1):S25–33.

    Article  Google Scholar 

  137. del Zoppo GJ. Aging and the neurovascular unit. Ann N Y Acad Sci. 2012;1268:127–33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  138. Redzic ZB, Rabie T, Sutherland BA, Buchan AM. Differential effects of paracrine factors on the survival of cells of the neurovascular unit during oxygen glucose deprivation. Int J Stroke. 2015;10(3):407–14.

    Article  PubMed  Google Scholar 

  139. Barakat R, Redzic Z. Differential cytokine expression by brain microglia/macrophages in primary culture after oxygen glucose deprivation and their protective effects on astrocytes during anoxia. Fluids Barriers CNS. 2015;12:6.

    Article  PubMed  PubMed Central  Google Scholar 

  140. Dirnagl U. Pathobiology of injury after stroke: the neurovascular unit and beyond. Ann N Y Acad Sci. 2012;1268:21–5.

    Article  PubMed  Google Scholar 

  141. Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 1999;22(9):391–7.

    Article  CAS  PubMed  Google Scholar 

  142. Moskowitz MA, Lo EH, Iadecola C. The science of stroke: mechanisms in search of treatments. Neuron. 2010;67(2):181–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Xing C, Hayakawa K, Lo EH. Mechanisms, Imaging, and Therapy in Stroke Recovery. Transl Stroke Res. 2016. doi:10.1007/s12975-016-0503-5.

  144. Jolkkonen J, Kwakkel G. Translational hurdles in stroke recovery studies. Transl Stroke Res. 2016;7(4):331–42.

    Article  CAS  PubMed  Google Scholar 

  145. Koh SH, Park HH. Neurogenesis in Stroke Recovery. Transl Stroke Res. 2016. doi:10.1007/s12975-016-0460-z.

  146. Commercial sources were utilized to estimate assay costs. Sources include Cedars-Sinai Medical Center Department of Comparative Medicine, Pharmaron Inc, Absorption Systems Inc, Ricera inc., Cyprotex Inc, and Oxygen BioResearch PVT Ltd.

Download references

Acknowledgments and Funding

This article was written without direct financial support from government sources (PAL). JHZ was supported by NIH (NS081740 and NS084921).

Author information

Authors and Affiliations

  1. Director of Translational Research, Department of Neurology & Neurosurgery, Advanced Health Sciences Pavilion, Suite 8305, Cedars-Sinai Medical Center, 127 S. San Vicente Blvd, Los Angeles, CA, 90048, USA

    Paul A. Lapchak

  2. Director, Center for Neuroscience Research, Loma Linda University School of Medicine, 11175 Campus St, Loma Linda, CA, 92350, USA

    John H. Zhang

Authors
  1. Paul A. Lapchak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John H. Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paul A. Lapchak.

Ethics declarations

Conflict of Interest

PAL is Editor-in-Chief, Journal of Neurology & Neurophysiology and Associate Editor, Translational Stroke Research; JHZ is Editor-in-Chief, Translational Stroke Research and Editor-in-Chief, Medical Gas Research.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lapchak, P.A., Zhang, J.H. The High Cost of Stroke and Stroke Cytoprotection Research. Transl. Stroke Res. 8, 307–317 (2017). https://doi.org/10.1007/s12975-016-0518-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12975-016-0518-y

Keywords

Search

Navigation