Thrombolytic Therapy for Acute Ischemic Stroke: Past and Future

Author(s): Keita Shibata, Terumasa Hashimoto, Takuro Miyazaki*, Akira Miyazaki, Koji Nobe.

Journal Name: Current Pharmaceutical Design

Volume 25 , Issue 3 , 2019


Abstract:

Background: Thromboembolic ischemic stroke, which is mainly caused by hypertension, as well as plasma dyslipidemia, arterial fibrillation and diabetes, is a leading cause of death in the US and other countries. Numerous clinical trials for thrombolytic drugs, which aimed to pharmacologically dissolve thrombi, were conducted in the 1950s, when the first thrombolytic therapy was performed.

Methods: In this study, we summarize the pathophysiologic features of ischemic stroke, and the history of thrombolytic therapy, and discuss the recent progress that has been made in the ongoing development of thrombolytic drugs.

Conclusion: Thrombolytic therapy is sometimes accompanied by harmful hemorrhagic insults; accordingly, a window of time wherein therapy can safely be performed has been established for this approach. Several basic and clinical studies are ongoing to develop next-generation thrombolytic drugs to expand the time window.

Keywords: Tissue plasminogen activator, tenecteplase, desmoteplase, SMTP-7, blood-brain barrier, cerebral infarction.

[1]
Heit JA. Venous thromboembolism: disease burden, outcomes and risk factors. J Thromb Haemost 2005; 3(8): 1611-7.
[2]
Lee LH, Gallus A, Jindal R, Wang C, Wu CC. Incidence of venous thromboembolism in Asian populations: A systematic review. Thromb Haemost 2017; 117(12): 2243-60.
[3]
Heit JA, Spencer FA, White RH. The epidemiology of venous thromboembolism. J Thromb Thrombolysis 2016; 41(1): 3-14.
[4]
Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: A systematic analysis for the Global Burden of Disease Study 2015. Lancet 2016; 388(10053): 1545-602.
[5]
Murray CJ, Lopez AD. Measuring the global burden of disease. N Engl J Med 2013; 369(5): 448-57.
[6]
Shichita T. Molecular and cellular mechanisms underlying the sterile inflammation after ischemic stroke. Nippon Yakurigaku Zasshi 2018; 151(1): 9-14.
[7]
Special report from the national institute of neurological disorders and stroke. Classification of cerebrovascular diseases III. Stroke 1990; 21(4): 637-76.
[8]
Murtagh B, Smalling RW. Cardioembolic stroke. Curr Atheroscler Rep 2006; 8(4): 310-6.
[9]
Arboix A, Alió J. Acute cardioembolic cerebral infarction: Answers to clinical questions. Curr Cardiol Rev 2012; 8(1): 54-67.
[10]
Timsit SG, Sacco RL, Mohr JP, et al. Early clinical differentiation of cerebral infarction from severe atherosclerotic stenosis and cardioembolism. Stroke 1992; 23(4): 486-91.
[11]
Lund RW. Lacunar infarction, mortality over time and mortality relative to other ischemic strokes. J Insur Med 2014; 44(1): 32-7.
[12]
Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics--2012 update: A report from the American Heart Association. Circulation 2012; 125(1): e2-e220.
[13]
Lastilla M. Lacunar infarct. Clin Exp Hypertens 2006; 28(3-4): 205-15.
[14]
Sacco S, Marini C, Totaro R, Russo T, Cerone D, Carolei A. A population-based study of the incidence and prognosis of lacunar stroke. Neurology 2006; 66(9): 1335-8.
[15]
Chamorro A, Sacco RL, Mohr JP, et al. Clinical-computed tomographic correlations of lacunar infarction in the Stroke Data Bank. Stroke 1991; 22(2): 175-81.
[16]
Petty GW, Brown RD Jr, Whisnant JP, Sicks JD, O’Fallon WM, Wiebers DO. Ischemic stroke subtypes: A population-based study of incidence and risk factors. Stroke 1999; 30(12): 2513-6.
[17]
Wardlaw JM, Smith C, Dichgans M. Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol 2013; 12(5): 483-97.
[18]
Peralta C, Werner P, Holl B, et al. Parkinsonism following striatal infarcts: incidence in a prospective stroke unit cohort. J Neural Transm (Vienna) 2004; 111(10-11): 1473-83.
[19]
Yoshitake T, Kiyohara Y, Kato I, et al. Incidence and risk factors of vascular dementia and Alzheimer’s disease in a defined elderly Japanese population: the Hisayama Study. Neurology 1995; 45(6): 1161-8.
[20]
Tanizaki Y, Kiyohara Y, Kato I, et al. Incidence and risk factors for subtypes of cerebral infarction in a general population: the Hisayama study. Stroke 2000; 31(11): 2616-22.
[21]
Tanaka H, Ueda Y, Hayashi M, et al. Risk factors for cerebral hemorrhage and cerebral infarction in a Japanese rural community. Stroke 1982; 13(1): 62-73.
[22]
Mankovsky BN, Ziegler D. Stroke in patients with diabetes mellitus. Diabetes Metab Res Rev 2004; 20(4): 268-87.
[23]
Abbott RD, Donahue RP, MacMahon SW, Reed DM, Yano K. Diabetes and the risk of stroke. The Honolulu Heart Program. JAMA 1987; 257(7): 949-52.
[24]
Shinohara Y, Gotoh F, Tohgi H, et al. Antiplatelet cilostazol is beneficial in diabetic and/or hypertensive ischemic stroke patients. Subgroup analysis of the cilostazol stroke prevention study. Cerebrovasc Dis 2008; 26(1): 63-70.
[25]
Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): A randomised controlled trial. Lancet 2005; 366(9493): 1279-89.
[26]
Lindenstrøm E, Boysen G, Nyboe J. Influence of total cholesterol, high density lipoprotein cholesterol, and triglycerides on risk of cerebrovascular disease: the Copenhagen City Heart Study. BMJ 1994; 309(6946): 11-5.
[27]
Iso H, Jacobs DR Jr, Wentworth D, Neaton JD, Cohen JD. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial. N Engl J Med 1989; 320(14): 904-10.
[28]
Amarenco P, Bogousslavsky J, Callahan A III, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006; 355(6): 549-59.
[29]
Amarenco P, Labreuche J. Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. Lancet Neurol 2009; 8(5): 453-63.
[30]
Vergouwen MD, de Haan RJ, Vermeulen M, Roos YB. Statin treatment and the occurrence of hemorrhagic stroke in patients with a history of cerebrovascular disease. Stroke 2008; 39(2): 497-502.
[31]
Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991; 22(8): 983-8.
[32]
Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: A meta-analysis. Ann Intern Med 1999; 131(7): 492-501.
[33]
Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365(10): 883-91.
[34]
Qizilbash N, Jones L, Warlow C, Mann J. Fibrinogen and lipid concentrations as risk factors for transient ischaemic attacks and minor ischaemic strokes. BMJ 1991; 303(6803): 605-9.
[35]
Kannel WB, Wolf PA, Castelli WP, D’Agostino RB. Fibrinogen and risk of cardiovascular disease. The Framingham Study. JAMA 1987; 258(9): 1183-6.
[36]
Love BB, Biller J, Jones MP, Adams HP Jr, Bruno A. Cigarette smoking. A risk factor for cerebral infarction in young adults. Arch Neurol 1990; 47(6): 693-8.
[37]
Iso H, Baba S, Mannami T, et al. Alcohol consumption and risk of stroke among middle-aged men: the JPHC Study Cohort I. Stroke 2004; 35(5): 1124-9.
[38]
Moskowitz MA, Lo EH, Iadecola C. The science of stroke: mechanisms in search of treatments. Neuron 2010; 67(2): 181-98.
[39]
Baron JC. Perfusion thresholds in human cerebral ischemia: historical perspective and therapeutic implications. Cerebrovasc Dis 2001; 11(Suppl. 1): 2-8.
[40]
Mies G, Iijima T, Hossmann KA. Correlation between peri-infarct DC shifts and ischaemic neuronal damage in rat. Neuroreport 1993; 4(6): 709-11.
[41]
Lo EH. A new penumbra: transitioning from injury into repair after stroke. Nat Med 2008; 14(5): 497-500.
[42]
Lipton P. Ischemic cell death in brain neurons. Physiol Rev 1999; 79(4): 1431-568.
[43]
Mehta SL, Manhas N, Raghubir R. Molecular targets in cerebral ischemia for developing novel therapeutics. Brain Res Brain Res Rev 2007; 54(1): 34-66.
[44]
Szydlowska K, Tymianski M. Calcium, ischemia and excitotoxicity. Cell Calcium 2010; 47(2): 122-9.
[45]
Japanese guideline for the management of stroke 2015.
[46]
Guidelines for the Management of Hypertension 2014.
[47]
Ouriel K. A history of thrombolytic therapy. J Endovasc Ther 2004; 11(Suppl. 2): II128-33.
[48]
Sikri N, Bardia A. A history of streptokinase use in acute myocardial infarction. Tex Heart Inst J 2007; 34(3): 318-27.
[49]
Tillett WS, Johnson AJ. McCARTY WR. The intravenous infusion of the streptococcal fibrinolytic principle (streptokinase) into patients. J Clin Invest 1955; 34(2): 169-85.
[50]
MacFarlane RG, Pilling J. Fibrinolytic activity of normal urine. Nature 1947; 159(4049): 779.
[51]
Sussman BJ, Fitch TS. Thrombolysis with fibrinolysin in cerebral arterial occlusion. J Am Med Assoc 1958; 167(14): 1705-9.
[52]
Meyer JS, Gilroy J, Barnhart MI, Johnson JF. Therapeutic thrombolysis in cerebral thromboembolism. Double-blind evaluation of intravenous plasmin therapy in carotid and middle cerebral arterial occlusion. Neurology 1963; 13: 927-37.
[53]
Fletcher AP, Alkjaersig N, Lewis M, et al. A pilot study of urokinase therapy in cerebral infarction. Stroke 1976; 7(2): 135-42.
[54]
Fujishima M, Omae T, Tanaka K, Iino K, Matsuo O, Mihara H. Controlled trial of combined urokinase and dextran sulfate therapy in patients with acute cerebral infarction. Angiology 1986; 37(7): 487-98.
[55]
Sikri N, Bardia A. A history of streptokinase use in acute myocardial infarction. Tex Heart Inst J 2007; 34(3): 318-27.
[56]
Tillett WS, Garner RL. The fibrinolytic activity of hemolytic streptococci. J Exp Med 1933; 58(4): 485-502.
[57]
Collen D, Lijnen HR. Thrombolytic agents. Thromb Haemost 2005; 93(4): 627-30.
[58]
Garner RL, Tillett WS. Biochemical studies on the fibrinolytic activity of hemolytic streptococci: I. Isolation and characterization of fibrinolysin. J Exp Med 1934; 60(2): 239-54.
[59]
Meyer JS, Gilroy J, Barnhart MI, Johnson JF. Anticoagulants plus streptokinase therapy in progressive stroke. JAMA 1964; 189: 373.
[60]
Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet 1988; 2(8607): 349-60.
[61]
Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Multicentre Acute Stroke Trial--Italy (MAST-I) Group. Lancet 1995; 346(8989): 1509-14.
[62]
Hommel M, Cornu C, Boutitie F, Boissel JP. Thrombolytic therapy with streptokinase in acute ischemic stroke. N Engl J Med 1996; 335(3): 145-50.
[63]
Gravanis I, Tsirka SE. Tissue-type plasminogen activator as a therapeutic target in stroke. Expert Opin Ther Targets 2008; 12(2): 159-70.
[64]
Moussaddy A, Demchuk AM, Hill MD. Thrombolytic therapies for ischemic stroke: Triumphs and future challenges. Neuropharmacology 2018; 134(Pt B): 272-9.
[65]
Rijken DC, Collen D. Purification and characterization of the plasminogen activator secreted by human melanoma cells in culture. J Biol Chem 1981; 256(13): 7035-41.
[66]
Collen D, Lijnen HR. Tissue-type plasminogen activator: A historical perspective and personal account. J Thromb Haemost 2004; 2(4): 541-6.
[67]
Van de Werf F, Ludbrook PA, Bergmann SR, et al. Coronary thrombolysis with tissue-type plasminogen activator in patients with evolving myocardial infarction. N Engl J Med 1984; 310(10): 609-13.
[68]
Van de Werf F, Bergmann SR, Fox KA, et al. Coronary thrombolysis with intravenously administered human tissue-type plasminogen activator produced by recombinant DNA technology. Circulation 1984; 69(3): 605-10.
[69]
Terashi A, Kobayashi Y, Katayama Y, Inamura K, Kazama M, Abe T. Clinical effects and basic studies of thrombolytic therapy on cerebral thrombosis. Semin Thromb Hemost 1990; 16(3): 236-41.
[70]
Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995; 333(24): 1581-7.
[71]
Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. JAMA 1995; 274(13): 1017-25.
[72]
Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet 1998; 352(9136): 1245-51.
[73]
Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359(13): 1317-29.
[74]
Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: A randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. JAMA 1999; 282(21): 2019-26.
[75]
Clark WM, Albers GW, Madden KP, Hamilton S. The rtPA (alteplase) 0- to 6-hour acute stroke trial, part A (A0276g) : results of a double-blind, placebo-controlled, multicenter study. Thromblytic therapy in acute ischemic stroke study investigators. Stroke 2000; 31(4): 811-6.
[76]
Davis SM, Donnan GA, Parsons MW, et al. Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): A placebo-controlled randomised trial. Lancet Neurol 2008; 7(4): 299-309.
[77]
Millán M, Remollo S, Quesada H, et al. Vessel patency at 24 hours and its relationship with clinical outcomes and infarct volume in REVASCAT trial (randomized trial of revascularization with Solitaire FR device versus best medical therapy in the treatment of acute stroke due to anterior circulation large vessel occlusion presenting within eight hours of symptom onset). Stroke 2017; 48(4): 983-9.
[78]
Al-Ajlan FS, Goyal M, Demchuk AM, et al. Intra-arterial therapy and post-treatment infarct volumes. Insights from the ESCAPE randomized controlled trial. Stroke 2016; 47(3): 777-81.
[79]
IST-3 collaborative group. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet 2012. 379: 2352-63.
[80]
Tanswell P, Modi N, Combs D, Danays T. Pharmacokinetics and pharmacodynamics of tenecteplase in fibrinolytic therapy of acute myocardial infarction. Clin Pharmacokinet 2002; 41(15): 1229-45.
[81]
Zhang L, Zhang ZG, Zhang C, Zhang RL, Chopp M. Intravenous administration of a GPIIb/IIIa receptor antagonist extends the therapeutic window of intra-arterial tenecteplase-tissue plasminogen activator in a rat stroke model. Stroke 2004; 35(12): 2890-5.
[82]
Haley EC Jr, Thompson JL, Grotta JC, et al. Phase IIB/III trial of tenecteplase in acute ischemic stroke: results of a prematurely terminated randomized clinical trial. Stroke 2010; 41(4): 707-11.
[83]
Parsons M, Spratt N, Bivard A, et al. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. N Engl J Med 2012; 366(12): 1099-107.
[84]
Huang X, Cheripelli BK, Lloyd SM, et al. Alteplase versus tenecteplase for thrombolysis after ischaemic stroke (ATTEST): A phase 2, randomised, open-label, blinded endpoint study. Lancet Neurol 2015; 14(4): 368-76.
[85]
Huang X, MacIsaac R, Thompson JL, et al. Tenecteplase versus alteplase in stroke thrombolysis: An individual patient data meta-analysis of randomized controlled trials. Int J Stroke 2016; 11(5): 534-43.
[86]
Logallo N, Novotny V, Assmus J, et al. Tenecteplase versus alteplase for management of acute ischaemic stroke (NOR-TEST): A phase 3, randomised, open-label, blinded endpoint trial. Lancet Neurol 2017; 16(10): 781-8.
[87]
Campbell BCV, Mitchell PJ, Churilov L, et al. Tenecteplase versus alteplase before thrombectomy for ischemic stroke. N Engl J Med 2018; 378(17): 1573-82.
[88]
Medcalf RL. Desmoteplase: discovery, insights and opportunities for ischaemic stroke. Br J Pharmacol 2012; 165(1): 75-89.
[89]
Reddrop C, Moldrich RX, Beart PM, et al. Vampire bat salivary plasminogen activator (desmoteplase) inhibits tissue-type plasminogen activator-induced potentiation of excitotoxic injury. Stroke 2005; 36(6): 1241-6.
[90]
Niego B, Freeman R, Puschmann TB, Turnley AM, Medcalf RL. t-PA-specific modulation of a human blood-brain barrier model involves plasmin-mediated activation of the Rho kinase pathway in astrocytes. Blood 2012; 119(20): 4752-61.
[91]
Mori E, Minematsu K, Nakagawara J, et al. Safety and tolerability of desmoteplase within 3 to 9 hours after symptoms onset in Japanese patients with ischemic stroke. Stroke 2015; 46(9): 2549-54.
[92]
Albers GW, von Kummer R, Truelsen T, et al. Safety and efficacy of desmoteplase given 3-9 h after ischaemic stroke in patients with occlusion or high-grade stenosis in major cerebral arteries (DIAS-3): A double-blind, randomised, placebo-controlled phase 3 trial. Lancet Neurol 2015; 14(6): 575-84.
[93]
Hacke W, Furlan AJ, Al-Rawi Y, et al. Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): A prospective, randomised, double-blind, placebo-controlled study. Lancet Neurol 2009; 8(2): 141-50.
[94]
Furlan AJ, Eyding D, Albers GW, et al. Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS): evidence of safety and efficacy 3 to 9 hours after stroke onset. Stroke 2006; 37(5): 1227-31.
[95]
Hacke W, Albers G, Al-Rawi Y, et al. The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): A phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke 2005; 36(1): 66-73.
[96]
von Kummer R, Mori E, Truelsen T, et al. Desmoteplase 3 to 9 Hours After Major Artery Occlusion Stroke: The DIAS-4 Trial (Efficacy and Safety Study of Desmoteplase to Treat Acute Ischemic Stroke). Stroke 2016; 47(12): 2880-7.
[97]
Hu W, Ohyama S, Hasumi K. Activation of fibrinolysis by SMTP-7 and -8, novel staplabin analogs with a pseudosymmetric structure. J Antibiot (Tokyo) 2000; 53(3): 241-7.
[98]
Hu W, Narasaki R, Nishimura N, Hasumi K. SMTP (Stachybotrys Microspora Triprenyl Phenol) enhances clot clearance in a pulmonary embolism model in rats. Thromb J 2012; 10(1): 2.
[99]
Hasumi K, Yamamichi S, Harada T. Small-molecule modulators of zymogen activation in the fibrinolytic and coagulation systems. FEBS J 2010; 277(18): 3675-87.
[100]
Shibata K, Hashimoto T, Nobe K, Hasumi K, Honda K. A novel finding of a low-molecular-weight compound, SMTP-7, having thrombolytic and anti-inflammatory effects in cerebral infarction of mice. Naunyn Schmiedebergs Arch Pharmacol 2010; 382(3): 245-53.
[101]
Hashimoto T, Shibata K, Nobe K, Hasumi K, Honda K. A novel embolic model of cerebral infarction and evaluation of SMTP-7, a novel fungal triprenyl phenol metabolite. J Pharmacol Sci 2010; 114: 41-9.
[102]
Ito A, Niizuma K, Shimizu H, Fujimura M, Hasumi K, Tominaga T. SMTP-7, a new thrombolytic agent, decreases hemorrhagic transformation after transient middle cerebral artery occlusion under warfarin anticoagulation in mice. Brain Res 2014; 1578: 38-48.
[103]
Shibata K, Hashimoto T, Nobe K, Hasumi K, Honda K. Neuroprotective mechanisms of SMTP-7 in cerebral infarction model in mice. Naunyn Schmiedebergs Arch Pharmacol 2011; 384(1): 103-8.
[104]
Miyazaki T, Kimura Y, Ohata H, et al. Distinct effects of tissue-type plasminogen activator and SMTP-7 on cerebrovascular inflammation following thrombolytic reperfusion. Stroke 2011; 42(4): 1097-104.
[105]
Akamatsu Y, Saito A, Fujimura M, et al. Stachybotrys microspora triprenyl phenol-7, a novel fibrinolytic agent, suppresses superoxide production, matrix metalloproteinase-9 expression, and thereby attenuates ischemia/reperfusion injury in rat brain. Neurosci Lett 2011; 503(2): 110-4.
[106]
Hashimoto T, Shibata K, Ohata H, Hasumi K, Honda K. Altered gene expression in an embolic stroke model after thrombolysis with tissue plasminogen activator and Stachybotrys microspora triprenyl phenol-7. J Pharmacol Sci 2014; 125(1): 99-106.
[107]
Matsumoto N, Suzuki E, Ishikawa M, Shirafuji T, Hasumi K. Soluble epoxide hydrolase as an anti-inflammatory target of the thrombolytic stroke drug SMTP-7. J Biol Chem 2014; 289(52): 35826-38.
[108]
Kito G, Nishimura A, Susumu T, et al. Experimental thromboembolic stroke in cynomolgus monkey. J Neurosci Methods 2001; 105(1): 45-53.
[109]
Sawada H, Nishimura N, Suzuki E, et al. SMTP-7, a novel small-molecule thrombolytic for ischemic stroke: A study in rodents and primates. J Cereb Blood Flow Metab 2014; 34(2): 235-41.
[110]
Edarovone Acute Infarction Study Group. Effect of a novel free radical scavenger, edaravone (MCI-186), on acute brain infarction. Randomized, placebo-controlled, double-blind study at multicenters. Cerebrovasc Dis 2003; 15(3): 222-9.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 25
ISSUE: 3
Year: 2019
Page: [242 - 250]
Pages: 9
DOI: 10.2174/1381612825666190319115018
Price: $58

Article Metrics

PDF: 33
HTML: 6
EPUB: 1

Special-new-year-discount