From: Adjunctive cytoprotective therapies in acute ischemic stroke: a systematic review
Compound | Mechanism of action | Year | Blinding\(^{\infty }\) | N\(^{\omega }\) | IVT/EVT\(^{\dagger }\) | Age\(^{\lambda }\) | NIHSS\(^{\rho }\) | T-t-T\(^{\xi }\) | Main outcome parameter | Effect size\(^{\pi }\) | P or ratio [CI]\(^{\ddagger }\) | Safety concern |
---|---|---|---|---|---|---|---|---|---|---|---|---|
(y) | (h) | (time point) | ||||||||||
Systemic heamodynamics | ||||||||||||
Atenolo [13] | \({\beta }_{1}\)-blocking agent | 1988 | ++ | 201 | +/− | 69 | ? | 24 | Mortality (30 d) | 14 \({\text{vs}}\) 25 | ? | Yes |
Candesartan [14] | AngII-R antagonist | 2003 | ++ | 339 | ? | 68 | ? | 30 | BI (30 d) | 89 \({\text{vs}}\) 87 | ns | No |
Candesartan [16] | 2011 | ++ | 2029 | +/− | 71 | ? | 18 | mRS (6 mo) | 2.0 \({\text{vs}}\) 2.1 | 1.13 (OR) [0.97–1.32]\(^{a}\) | No | |
DCLHb [18] | Increase blood oxygen level | 1999 | + | 85 | +/− | 66 | ? | ? | mRS \(\ge\)3 (90 d) | 51% \({\text{vs}}\) 85% | 0.002 | Yes |
Irbesartan [19] | AngII-R antagonist | 2011 | ++ | 43 | +/− | 69 | 7 | 53 | Infarct volume (30 d) | 280 \({\text{vs}}\) 822 | 0.63\(^{a}\) | No |
Lifarizine [20] | Sodium and calcium antagonist | 1996 | ++ | 117 | ? | 69 | ? | ? | Independent mRS (90 d) | \(\Delta\)placebo-drug = 16% | 0.522 | No |
Lisinopri [21] | ACE inhibitor | 2007 | ++ | 40 | ? | 74 | 11 | 19 | mRS \(\le\)2 (90 d) | 63% \({\text{vs}}\) 60% | 0.56\(^{a}\) | No |
Magnesium sulfate [22] | Multiple action sides resulting in vasodilatation and increased CBF | 2004 | ++ | 2386 | +/− | 70 | ? | 7 | mRS \(\ge\)2 (90 d) | 72% \({\text{vs}}\) 70% | 0.95 (OR) [0.80–1.13] | Yes |
Magnesium sulfate [23] | 2015 | ++ | 1700 | +/− | 69 | 11 | 45 min | mRS (90 d) | 2.7 \({\text{vs}}\) 2.7 | 1\(^{a}\) | No | |
Nimodipine [24] | Calcium antagonist | 1988 | ++ | 186 | − | 69 | ? | ? | Mortality (6 mo) | 28% \({\text{vs}}\) 17% | 0.046 | No |
Nimodipine [24] | 1989 | ++ | 41 | − | 63 | ? | ? | mMS (28 d) | 78 \({\text{vs}}\) 89 | <0.04 | No | |
Nimodipine [195] | 1990 | ++ | 52 | ? | 65 | ? | 19 | MS improvement (4 mo) | 86% \({\text{vs}}\) 75% | ns | No | |
Nimodipine [196] | 1990 | ++ | 1215 | ? | 73 | ? | ? | BI \(\ge\)60 (6 mo) | 58% \({\text{vs}}\) 55% | 0.31 | No | |
Nimodipine [197] | 1992 | ++ | 1064 | ? | 66 | ? | 28 | Mortality (6 mo) | 16% \({\text{vs}}\) 14% | ns | No | |
Nimodipine [198] | 1993 | ++ | 164 | ? | 72 | ? | ? | Mortality (28 d) | 15% \({\text{vs}}\) 10% | ns | No | |
Nimodipine [27] | 1994 | ++ | 350 | ? | 58 | ? | 20 | mRS \(\le\)2 (12 mo) | 64% \({\text{vs}}\) 66% | ns | Yes | |
Nimodipine [26] | 1994 | ++ | 295 | ? | 72 | ? | 11 | BI (21 d) | 22 \({\text{vs}}\) 10 | 0.003\(^{a}\) | No | |
Nimodipine [199] | 2000 | ++ | 153 | ? | 59 | ? | ? | Infarct volume (90 d) | 10.2 \({\text{vs}}\) 4.4 | ns | ? | |
Nimodipine [200] | 2001 | ++ | 454 | ? | 71 | ? | ? | mRS >3 (90 d) | 27% \({\text{vs}}\) 32% | 1.2 (RR) [0.9−1.6] | No | |
Piracetam [28] | Positive allosteric AMPA-R modulator | 1997 | ++ | 927 | − | 70 | ? | 7 | BI (90 d) | 53 \({\text{vs}}\) 56 | 0.33 | No |
Propranolol [13] | \(\beta\)-blocking agent | 1988 | ++ | 201 | +/− | 68 | ? | 25 | Mortality (30 d) | 14 \({\text{vs}}\) 27 | ? | Yes |
Excitotoxicity | ||||||||||||
Aptiganel HCl [34] | NMDA-R antagonist | 2001 | ++ | 628 | − | 72 | 12 | ? | Phase II part: \(\Delta\)NIHSS (7 d) | − 4 \({\text{vs}}\)− 3.5 | 0.41 | Yes |
Phase III part: mRS (90 d) | 3.1 \({\text{vs}}\) 3.3 | 0.44 | ||||||||||
Clomethiazole [35] | GABA-R agonist | 1999 | ++ | 1360 | − | 71 | ? | ? | BI \(\ge\)60 (90 d) | 55% \({\text{vs}}\) 56% | 0.649 | No |
Clomethiazole [37] | 2001 | ++ | 190 | + | 67 | 14 | 5.4 | BI \(\ge\)60 (90 d) | 67% \({\text{vs}}\) 66% | 0.94 (OR) [0.51–1.72] | No | |
Clomethiazole [36] | 2002 | ++ | 1198 | − | 72 | 17 | ? | BI \(\ge\)60 (90 d) | 46% \({\text{vs}}\) 42% | 0.11 | No | |
Diazepam [38] | GABA-R agonist | 2006 | ++ | 849 | ? | 72 | ? | ? | mRS <3 (90 d) | 49% \({\text{vs}}\) 52% | 1.14 (OR) [0.87−1.49] | No |
Fanapanel [39] | AMPA-R antagonist | 2002 | ++ | 61 | – | 67 | 6 | 17 | NIHSS (30 d) | ? | 0.07 | Yes |
Gavestinel (GV150526) [40] | NMDA-R antagonist | 2001 | ++ | 1367 | ? | 72 | 12 | 5.2 | mRS \(\le\)1 (90 d) | 26% \({\text{vs}}\) 29% | 0.3 | No |
Lanicemine HCl [41] | NMDA-R antagonist | 2002 | ++ | 103 | – | 67 | 9 | ? | \(\Delta\)NIHSS \(\ge\)4 (30 d) | ? | 0.563 (OR) [0.24−1.31] | Yes |
Lithium [42] | NMDA-R antagonist | 2014 | ++ | 66 | +/– | 62 | 7 | ? | \(\Delta\)NIHSS (30 d) | − 1.64 \({\text{vs}}\) − 2.34 | 0.402 | No |
Lubeluzole [45] | Indirect NMDA-R antagonist | 1996 | ++ | 193 | ? | 71 | 15 | 4.3 | \(\Delta\)NIHSS (28 d) | − 5.8 \({\text{vs}}\) − 6.4 | ns | Yes |
Lubeluzole [43] | 1997 | ++ | 700 | +/− | 71 | 15 | 4.6 | mRS \(\ge\)3 (90 d) | 44% \({\text{vs}}\) 42% | 0.04 | No | |
Lubeluzole [44] | 1998 | ++ | 725 | − | 70 | ? | 4.4 | mRS 3−5 (90 d) | 48% \({\text{vs}}\) 52% | ns | No | |
Nalmefene [46] | Opioid-R antagonist | 2000 | ++ | 330 | +/– | 70 | 12 | 4.4 | \(\Delta\)NIHSS \(\ge\)4 (90 d) | 65% \({\text{vs}}\) 64% | 0.88 | No |
Selfotel [48] | NMDA-R antagonist | 2000 | ++ | 567 | ? | 69 | 14 | 4.5 | BI \(\ge\)60 (90 d) | 61% \({\text{vs}}\) 58% | 0.49 | Yes |
Oxidative and nitrosative stress | ||||||||||||
Disufenton sodium [50] | Free radical scavenger | 2001 | ++ | 147 | − | 68 | 8 | 15 | \(\Delta\)NIHSS (30 d) | − 3 \({\text{vs}}\) − 3 | ns | No |
Disufenton sodium [53] | 2006 | ++ | 1699 | +/− | 68 | 13 | 3.8 | mRS (90 d) | \(\le\)1: 31% \({\text{vs}}\) 33% | 1.20 (OR) [1.01−1.42] | No | |
Disufenton sodium [54] | 2007 | ++ | 3195 | +/– | 69 | 13 | 3.8 | mRS (90 d) | \(\le\)1: 29% \({\text{vs}}\) 27% | 0.94 (OR) [0.83−1.06]\(^{a}\) | No | |
Disufenton sodium [51] | 2008 | ++ | 5028 | +/− | 71 | 13 | 3.8 | mRS (90 d) | \(\le\)1: 29% \({\text{vs}}\) 29% | 1.02 (OR) [0.92−1.13]\(^{a}\) | No | |
Ebselen [58] | Free radical scavenger | 1998 | ++ | 300 | − | 65 | ? | 29 | BI \(\ge\)75 (90 d) | 50% \({\text{vs}}\) 64% | 0.012 | No |
Ebselen [57] | 1999 | ++ | 99 | +/− | 99 | ? | 9 | Infarct volume (30 d) | 12.74 \({\varvec{{\text{vs}}}}\) 8.30 | 0.034 | No | |
Edaravone [59] | Free radical scavenger | 2003 | ++ | 250 | − | 66 | 7 | 36 | mRS (90 d) | 2.2 \({\varvec{{\text{vs}}}}\) 1.8 | 0.038 | No |
Epigallocatechin Gallate [60] | Free radical scavenger | 2017 | ++ | 71 | + | 65 | 15 | ? | NIHSS \(\le\)10 (7 d) | 41% \({\text{vs}}\) 45% | ns | No |
Glyceryl Trinitrate [61] | Free radical scavenger | 2015 | ++ | 4011 | +/− | 70 | 11 | 26 | mRS (90 d) | ? | 1.01 (OR) [0.91–1.13]\(^{a}\) | No |
Glyceryl Trinitrate [63] | 2019 | + | 852 | +/− | 74 | 10 | 1.1 | mRS (90 d) | 3 \({\text{vs}}\) 3 | 0.083\(^{a}\) | No | |
Uric−acid [68] | Free radical scavenger | 2014 | ++ | 411 | + | 77 | 13 | 3 | mRS (90 d) | 3 \({\varvec{{\text{vs}}}}\) 2 | 0.045\(^{a}\) | No |
Tirilazad mesylate [70] | Free radical scavenger | 1994 | ++ | 111 | +/− | 66 | 8 | 8.5 | NIHSS (90 d) | 1 \({\text{vs}}\) 2 | 0.105 | No |
Tirilazad mesylate [71] | 1996 | ++ | 556 | − | 69 | 10 | 4.3 | BI (90 d) | 95 \({\text{vs}}\) 95 | 0.87 (OR) [0.60−1.25]\(^{a}\) | No | |
Tirilazad mesylate [72] | 2002 | + | 368 | ? | 70 | ? | ? | Infarct volume (8 d) | 37mL \({\text{vs}}\) 43mL | 0.55 | ? | |
Blood–brain barrier and vasogenic edema | ||||||||||||
Albumin+Ringers-glucose [10] | Colloid-osmotic pressure modifier | 1992 | − | 297 | +/− | 75 | ? | ? | Mortality (90 d) | 21% \({\text{vs}}\) 17% | ns | No |
Albumin [80] | 2011 | ++ | 424 | +/− | 70 | 11 | 3.5 | Mortality (90 d) | 13% \({\text{vs}}\) 21% | 1.55 (RR) [1.01−2.39] | Yes | |
Albumin [77] | 2013 | ++ | 841 | +/− | 64 | 11 | ? | Good outcome (90 d) | 44% \({\text{vs}}\) 44% | 0.96 (RR) [0.84−1.10]\(^{a}\) | Yes | |
Citicoline [83] | Cell membrane stabilizer | 1997 | ++ | 259 | ? | 68 | 13 | 14.5 | mRS (30 d) | 3.1 \({\varvec{{\text{vs}}}}\) 2.5 | 0.03\(^{a}\) | No |
Citicoline [85] | 2000 | ++ | 81 | ? | 70 | 12 | 14.3 | \(\Delta\)Infarct volume (30 d) | 18.9 \({\text{vs}}\) 11.3 | 0.18 | No | |
Citicoline [84] | 2001 | ++ | 899 | ? | 68 | 14 | 13 | Infarct volume (30 d) | 58.9 \({\text{vs}}\) 57.7 | 0.80 | No | |
Citicoline [86] | 2012 | ++ | 2298 | +/− | 73 | 15 | 6.7 | mRS \(\le\)1 (90 d) | 18% \({\text{vs}}\) 18% | 1.07 (OR) [0.85−1.36] | No | |
Fasudil [88] | Rho-kinase inhibitor | 2005 | ++ | 160 | − | 68 | ? | 22 | \(\Delta\)mRS \(\le\)− 2 (30 d) | 44% \({\varvec{{\text{vs}}}}\) 63% | 0.0015 | No |
Glyburide [95] | K\(_{ATP}\)/NC\(_{Ca-ATP}\) channel inhibitor | 2016 | ++ | 77 | +/− | 60 | 20 | 9 | mRS \(\le\)3 (90 d) | 41% \({\text{vs}}\) 39% | 0.87 (OR) [0.32−2.32]\(^{a}\) | No |
Imatinib [96] | Tyrosine kinase inhibitor | 2017 | +/− | 60 | + | 73 | 12 | 4 | mRS \(\le\)2 (90 d) | 61% \({\text{vs}}\) 78% | 0.296\(^{a}\) | No |
Sodium tanshinone IIA sulfonate [98] | Downregulation MMP9 | 2017 | ++ | 42 | + | 64 | 8 | 3.5 | mRS \(\le\)1 (90 d) | 43% \({\varvec{{\text{vs}}}}\) 76% | 0.028 | ? |
Neurogenesis/-regeneration/-recovery | ||||||||||||
Cerebrolysin [103] | Multiple neurotrophic factors | 2012 | ++ | 1067 | +/− | 65 | 9 | 8 | mRS (90 d) | 2 \({\text{vs}}\) 2 | ns | No |
Cerebrolysin [104] | 2012 | ++ | 119 | + | 66 | 12 | 2 | mRS \(\le\)1 (90 d) | 55% \({\text{vs}}\) 53% | 0.13 (OR) [−0.55 to 0.88] | No | |
Cerebrolysin [106] | 2017 | ++ | 100 | − | 68 | 10 | ? | mRS \(\le\)1 (30 d) | 26% \({\varvec{{\text{vs}}}}\) 31% | 0.01 | No | |
Cerebrolysin [105] | 2016 | ++ | 40 | +/− | 67 | 10 | 7 | NIHSS (21 d) | 7.3 \({\varvec{{\text{vs}}}}\) 5.9 | <0.05 | No | |
Choriogonadotropin + epoetin-\(\alpha\)[108] | Neural stem cell proliferation stimulator | 2014 | ++ | 96 | – | 58 | 13 | 38 | \(\Delta\)NIHSS (90 d) | − 8 \({\text{vs}}\) − 8 | 0.31\(^{a}\) | No |
Cutamesine [109] | \(\alpha\)-1 receptor (Sig-1R) agonist | 2014 | ++ | 60 | +/− | 67 | 9 | 59 | mRS \(\le\)1 (56 d) | 19% \({\text{vs}}\) 42% | 2.68 (OR) [0.62−11.49]\(^{a}\) | No |
Dexamphetamine [110] | TAAR1 agonist | 2003 | ++ | 45 | ? | 67 | ? | 53 | BI (90 d) | ? | ns | No |
DL-3-n-butylphthalide (NBP) [105] | Multiple neuroprotective effects | 2016 | ++ | 40 | +/− | 67 | 11 | 7 | NIHSS (21 d) | 7.3 \({\varvec{{\text{vs}}}}\) 5.5 | <0.01 | No |
Erythropoietin [111] | Erythropoiesis stimulator | 2009 | ++ | 460 | +/− | 68 | 13 | 4 | Lesion volume (7 d) | 91 \({\varvec{{\text{vs}}}}\) 86 | 0.67 | Yes |
Filgrastim [113] | Granulocyte colony stimulating factor | 2012 | ++ | 60 | +/− | 72 | 10 | 233 | Lesion volume (90 d) | 5.2 \({\varvec{{\text{vs}}}}\) 27.6 | 0.51 | No |
Filgrastim [112] | 2013 | ++ | 323 | +/− | 69 | 12 | 7 | Lesion volume (30 d) | 65.9 \({\text{vs}}\) 59.0 | 0.44\(^{a}\) | No | |
GSK-249320 [114] | Blocking Myelin-associated glycoprotein | 2017 | ++ | 134 | +/− | 68 | 10 | 52 | mRS (90 d) | 2.8 \({\text{vs}}\) 2.7 | ns | No |
Kallikrein [117] | Serine proteinase | 2011 | ++ | 44 | ? | 68 | 10 | 42 | \(\Delta\)Lesion volume (14 d) | 0 \({\varvec{{\text{vs}}}}\) 81.5 | 0.009 | No |
Neurotropin [120] | Neurotrophic factor | 1994 | ++ | 144 | +/− | 72 | ? | ? | \(\Delta\)Lesion volume (11 d) | 0.17 \({\varvec{{\text{vs}}}}\) − 1.27 | 0.02 | No |
Neuroinflammation | ||||||||||||
Atorvastatin [19] | HMG-CoA reductase inhibitor | 2011 | ++ | 81 | +/− | 67 | 6 | 53 | Lesion volume (30 d) | 280 \({\text{vs}}\) 462 | 0.792\(^{a}\) | No |
Atorvastatin [127] | 2011 | ++ | 62 | – | 75 | 13 | 7 | Lesion volume (3 d) | 16.2 \({\text{vs}}\) 30.4 | 0.33 | No | |
Ceftriaxone [128] | Bacterial cell wall synthesis inhibitor | 2015 | + | 2538 | +/− | 74 | 5 | ? | mRS \(\le\)2 (90 d) | 60% \({\text{vs}}\) 62%; 0.94 (OR) | [0.80–1.11] | No |
Cyclosporine [132] | Calcineurin inhibitor | 2015 | + | 110 | + | 68 | 13 | 2.5 | \(\Delta\)Lesion volume (30 d) | 28.8 \({\text{vs}}\) 21.8 | 0.18 | No |
Enlimomab [136] | ICAM antibody | 2001 | ++ | 625 | – | 69 | 15 | 4.5 | mRS \(\le\)1 (90 d) | 34% \({\text{vs}}\) 27% | 0.004\(^{a}\) | Yes |
Fingolimod [137] | S1P-R1 antagonist | 2015 | +/− | 47 | + | 59 | 12 | 3 | Lesion volume (7 d) | 12.1 \({\varvec{{\text{vs}}}}\) − 2.3 | <0.01 | No |
Minocycline [139] | Microglia activation inhibiton | 2007 | +/− | 152 | +/− | 66 | 8 | 13 | mRS (90 d) | 2.1 \({\varvec{{\text{vs}}}}\) 0.9 | <0.0001 | No |
Minocycline [140] | 2013 | +/− | 95 | +/− | 68 | 9 | 11 | mRS \(\le\)2 (90 d) | 33% \({\text{vs}}\) 29% | 0.94 (RR) [0.71–1.25] | No | |
Moxifloxacin [141] | Antibiotic | 2008 | ++ | 79 | ? | 72 | 16 | ? | BI \(\ge\)60 (6 mo) | 55% \({\text{vs}}\) 64% | 0.57 | No |
Natalizumab [147] | \(\alpha\)4 integrin antagonist | 2017 | ++ | 161 | +/− | 70 | 13 | 7 | \(\Delta\)Lesion volume (30 d) | 4 \({\text{vs}}\) 4 | 0.68 | No |
Simvastatin [148] | HMG-CoA reductase inhibitor | 2008 | ++ | 60 | – | 73 | 12 | ? | mRS (90 d) | 3 \({\text{vs}}\) 3 | 0.86 | Yes |
Simvastatin [149] | 2016 | ++ | 104 | +/− | 74 | 7 | 7 | mRS\(\le\)2 (90 d) | 70% \({\text{vs}}\) 69% | 0.99 (OR) [0.35−2.78]\(^{a}\) | No | |
UK-279,276 [151] | Neutrophil inhibitor | 2003 | ++ | 746 | +/− | 72 | 13 | 4 | Mortality (90 d) | 15% \({\text{vs}}\) 17% | ns | No |
Additional compounds | ||||||||||||
Acetaminophen[153] | Inhibit cyclo-oxygenases or serotonerge system | 2001 | ++ | 42 | ? | 70 | 5 | ? | mRS (5 d) | ? | ns | No |
Acetaminophen [152] | 2009 | ++ | 1400 | +/− | 70 | 7 | 6 | mRS \(\le\)2 (90 d) | 50% \({\text{vs}}\) 51% | 1.09 (OR) [0.88−1.33] | No | |
DP-b99 [154] | Zinc and calcium ion chelator | 2008 | ++ | 150 | – | 73 | 12 | 6 | mRS \(\le\)1 (90 d) | 16% \({\varvec{{\text{vs}}}}\) 31% | 0.05 | No |
Reptinotan [155] | (5-HT)1A receptor agonist | 2009 | ++ | 681 | +/− | 70 | 15 | ? | mRS \(\le\)2 (90 d) | 38% \({\text{vs}}\) 32% | 0.136\(^{a}\) | No |