- 1. National Stroke Research Institute, Melbourne, Australia 2. School of Molecular and Clinical Medicine, University of Edinburgh, Edinburgh, UK 3. Department of Medicine, University of Melbourne, Melbourne, Australia;
FK506是治疗急性卒中的一种候选用药。决定一种药物是否可以用于临床试验，应当以全面的、无偏倚的动物实验数据的评估为依据，同时还应考虑到这些数据的局限性。这种评估不但应包括药物疗效，而且也应包括药效在体内的特征和局限性。本研究应用系统评价和Meta分析的方法对FK506在卒中动物模型中保护作用的证据进行评价。总共纳入了29个描述了实验步骤的研究，包括1759只动物。结果显示，FK506疗效的点估计值（结局指标的改善）是31.3%[95%CI（0.272~0.354）]。在采用氯胺酮麻醉和短暂性脑缺血的动物实验中，FK506的疗效更高，在使用大鼠，合并其他疾病的动物及仅以梗死面积为疗效指标的实验中，FK506疗效较低。已发表的实验研究质量均接近临床试验标准，但在高质量的研究中，FK506的疗效较低。FK506在实验性脑卒中的研究中，虽然显示出有明显的疗效，但是应注意由于研究质量和可能的发表偏倚等因素的影响，FK506的疗效可能被过高估计。
Citation： Malcolm R Macleod,Tori OCollins,Laura L Horky,David W Howells,Geoffrey A Donnan. FK506对实验性卒中疗效的系统评价和Meta分析. Chinese Journal of Evidence-Based Medicine, 2006, 06(6): 430-438. doi: Copy
| 1. | Aoyama S, Katayama Y, Terashi A (1997) The effect of FK 506, an immunosuppressant, on cerebral infarction volume in focal cerebral ischemia in rats. Nippon Ika Daigaku Zasshi—J Nippon Med School 64:416–21. |
| 2. | Arii T, Kamiya T, Arii K, Ueda M, Nito C, Katsura KI, Katayama Y (2001) Neuroprotective effect of immunosuppressant FK506 in transient focal ischemia in rat: therapeutic time window for FK506 in transient focal ischemia. Neurol Res 23:755–60. |
| 3. | Aronowski J, Grotta JC, Strong R, Waxham MN (2000) Interplay between the gamma isoform of PKC and calcineurin in regulation of vulnerability to focal cerebral ischemia. J Cereb Blood Flow Metab 20:343–9. |
| 4. | Bebarta V, Luyten D, Heard K (2003) Emergency medicine animal research: does use of randomization and blinding affect the results? Acad Emerg Med 10:684–7. |
| 5. | Bochelen D, Rudin M, Sauter A (1999) Calcineurin inhibitors FK506 and SDZ ASM 981 alleviate the outcome of focal cerebral ischemic/reperfusion injury. J Pharmacol Exp Ther 288:653–9. |
| 6. | Brecht S, Schwarze K, Waetzig V, Christner C, Heiland S, Fischer G, Sartor K, Herdegen T (2003) Changes inpeptidyl-prolyl cis/trans 7isomerase activity and FK506 binding protein expression following neuroprotection by FK506 in the ischemic rat brain. Neuroscience 120:1037–48. |
| 7. | Butcher SP, Henshall DC, Teramura Y, Iwasaki K, Sharkey J (1997) Neuroprotective actions of FK506 in experimental stroke: in vivo evidence against an antiexcitotoxic mechanism. J Neurosci 17:6939–46. |
| 8. | Chang ML, Yang J, Kem S, Klaidman L, Sugawara T, Chan PH, Adams Jr JD (2002) Nicotinamide and ketamine reduce infarct volume and DNA fragmentation in rats after brain ischemia and reperfusion. Neurosci Lett 322:137–40. |
| 9. | Chung SY, Lin JY, Lin MC, Liu HM, Wang MF, Cheng FC (2004) Synergistic efficacy of magnesium sulfate and FK506 on cerebral ischemia-induced infarct volume in gerbil. Med Sci Monit 10:BR105–8. |
| 10. | DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–88. |
| 11. | Ebisu T, Katsuta K, Fujikawa A, Aoki I, Umeda M, Naruse S, Tanaka C (2001) Early and delayed neuroprotective effects of FK506 on experimental focal ischemia quantitatively assessed by diffusion-weighted MRI. Magn Reson Imaging 19:153–60. |
| 12. | Egger M, Davey Smith G, Altman DG (2001) Systematic Reviews in Health Care: Meta-analysis in Context. London: BMJ Books. |
| 13. | Engelter ST, Provenzale JM, Petrella JR, DeLong DM, Alberts MJ (2003) Infarct volume on apparent diffusion coefficient maps correlates with length of stay and outcome after middle cerebral artery stroke. Cerebrovasc Dis 15:188–91. |
| 14. | Fredduzzi S, Mariucci G, Tantucci M, Del Soldato P, Ambrosini MV (2001) Nitro-aspirin (NCX4016) reduces brain damage induced by focal cerebral ischemia in the rat. Neurosci Lett 302:121–4. |
| 15. | Furuichi Y, Katsuta K, Maeda M, Ueyama N, Moriguchi A, Matsuoka N, Goto T, Yanagihara T (2003a) Neuroprotective action of tacrolimus (FK506) in focal and global cerebral ischemia in rodents: dose dependency, therapeutic time window and long-term efficacy. Brain Res 965:137–45. |
| 16. | Furuichi Y, Maeda M, Moriguchi A, Sawamoto T, Kawamura A, Matsuoka N, Mutoh S, Yanagihara T (2003b) Tacrolimus, a potential neuroprotective agent, ameliorates ischemic brain damage and neurologic deficits after focal cerebral ischemia in nonhuman primates. J Cereb Blood Flow Metab 23:1183–94. |
| 17. | Horn J, de Haan RJ, Vermeulen M, Luiten PG, Limburg M (2001) Nimodipine in animal model experiments of focal cerebral ischemia: a systematic review. Stroke 32:2433–8. |
| 18. | Janelidze S, Yoshimoto T, Kristian T, Siesjo BK (1999) The role of strain differences on the efficacy of PBN (N-tertbutyl-phenylnitrone) and FK506 treatment in transient focal ischemia. J Cereb Blood Flow Metab 19(Suppl 1):S171. |
| 19. | Kuroda S, Janelidze S, Siesjo BK (1999) The immunosuppressants cyclosporin A and FK506 equally ameliorate brain damage due to 30-min middle cerebral artery occlusion in hyperglycemic rats. Brain Res 835:148–53. |
| 20. | Kuroda S, Siesjo BK (1996) Postischemic administration of FK506 reduces infarct volume following transient focal brain ischemia. Neurosci Res Commun 19:83–90. |
| 21. | Labiche LA, Grotta JC (2004) Clinical trials for cytoprotection in stroke. NeuroRx 1:46–70. |
| 22. | Liu J, Farmer Jr JD, Lane WS, Friedman J, Weissman I, Schreiber SL (1991) Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell 66:807–15. |
| 23. | Macleod MR, Allsopp TE, McLuckie J, Kelly JS (2001) Serum withdrawal causes apoptosis in SHSY 5Y cells. Brain Res 889:308–15. |
| 24. | Macleod MR, O’Collins T, Horky LL, Howells DW, Donnan GA (2005) Systematic review and meta-analysis of the efficacy of melatonin in experimental stroke. J Pineal Res 38:35–41. |
| 25. | Macleod MR, O’Collins T, Howells DW, Donnan GA (2004) Pooling of animal experimental data reveals influence of study design and publication bias. Stroke 35:1203–8. |
| 26. | Maeda M, Furuichi Y, Ueyama N, Moriguchi A, Satoh N, Matsuoka N, Goto T, Yanagihara T (2002) A combined treatment with tacrolimus (FK506) and recombinant tissue plasminogen activator for thrombotic focal cerebral ischemia in rats: increased neuroprotective efficacy and extended therapeutic time window. J Cereb Blood Flow Metab 22:1205–11. |
| 27. | Martin D, Lodge D (1985) Ketamine acts as a noncompetitive N-methyl-D-aspartate antagonist on frog spinal cord in vitro. Neuropharmacology 24:999–1003. |
| 28. | McCarter JF, McGregor AL, Jones PA, Sharkey J (2001) FK 506 protects brain tissue in animal models of stroke. Transplant Proc 33:2390–2. |
| 29. | McGregor AL, Marston HM, Sharkey J (2001) Reduced mortality and improved functional outcome associated with FK506 treatment in a mouse model of MCA occlusion. J Cereb Blood Flow Metab 21(Suppl 1):S244. |
| 30. | Miyazawa N, Saji H, Takaishi Y, Nukui H (2000) Protective effect of FK506 in the reperfusion model after shortterm occlusion of middle cerebral artery in the rat: assessment by autoradiography using [125I]PK-11195. Neurol Res 22:630–3. |
| 31. | Moher D, Schulz KF, Altman DG (2001) The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials. Lancet 357:1191–4. |
| 32. | Murphy GJ, Waller JR, Sandford RS, Furness PN, Nicholson ML (2003) Randomized clinical trial of the effect of microemulsion cyclosporin and tacrolimus on renal allograft fibrosis. Br J Surg 90:680–6. |
| 33. | Nalesnik MA, Lai HS, Murase N, Todo S, Starzl TE (1990) The effect of FK 506 and CyA on the Lewis rat renal ischemia model. Transplant Proc 22:87–9. |
| 34. | NINDS (2000) Effect of intravenous recombinant tissue plasminogen activator on ischemic stroke lesion size measured by computed tomography. Stroke 31:2912–9. |
| 35. | Nito C, Kamiya T, Ueda M, Amemiya S, Inaba T, Katayama Y (2002) Mild hypothermia enhances neuroprotective effects of immunosuppressant FK506 following transient focal ischemia in rats. Society for Neuroscience Abstract No 491.8. |
| 36. | Nito C, Kamiya T, Ueda M, Arii T, Katayama Y (2004) Mild hypothermia enhances the neuroprotective effects of FK506 and expands its therapeutic window following transient focal ischemia in rats. Brain Res 1008:179–85. |
| 37. | Pound P, Ebrahim S, Sandercock P, Bracken MB, Roberts I (2004) Where is the evidence that animal research benefits humans? BMJ 328:514–7. |
| 38. | Sharkey J, Butcher SP (1994) Immunophilins mediate the neuroprotective effects of FK506 in focal cerebral ischaemia. Nature 371:336–9. |
| 39. | Sharkey J, Crawford JH, Butcher SP, Marston HM (1996) Tacrolimus (FK506) ameliorates skilled motor deficits produced by middle cerebral artery occlusion in rats. Stroke 27:2282–6. |
| 40. | Sharkey J, Teramura Y, Iwasaki K, Butcher SP (1997) Brain levels of FK506 and neuroprotection in experimental stroke. Br J Pharmacol 122:329. |
| 41. | Shichinohe H, Kuroda S, Abumiya T, Ikeda J, Kobayashi T, Yoshimoto T, Iwasaki Y (2004) FK506 reduces infarct volume due to permanent focal cerebral ischemia by maintaining BAD turnover and inhibiting cytochrome c release. Brain Res 1001:51–9. |
| 42. | Stroke Academic Industry Roundtable (1999) Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 30:2752–8. |
| 43. | Suzuki S, Toledo-Pereyra LH, Rodriguez FJ, Cejalvo D (1993) Neutrophil infiltration as an important factor in liver ischemia and reperfusion injury. Modulating effects of FK506 and cyclosporine. Transplantation 55:1265–72. |
| 44. | Takamatsu H, Kondo K, Ikeda Y, Umemura K (1998) Neuroprotective effects depend on the model of focal ischemia following middle cerebral artery occlusion. Eur J Pharmacol 362:137–42. |
| 45. | Takamatsu H, Tsukada H, Noda A, Kakiuchi T, Nishiyama S, Nishimura S, Umemura K (2001) FK506 attenuates early ischemic neuronal death in a monkey model of stroke. J Nucl Med 42:1833–40. |
| 46. | The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group (1995) Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 333:1581–8. |
| 47. | Tong DC, Yenari MA, Albers GW, O’Brien M, Marks MP, Moseley ME (1998) Correlation of perfusion- anddiffusion-weighted MRI with NIHSS score in acute (o6.5 hour) ischemic stroke. Neurology 50:864–70. |
| 48. | Toung TJ, Bhardwaj A, Dawson VL, Dawson TM, Traystman RJ, Hurn PD (1999) Neuroprotective FK506 does not alter in vivo nitric oxide production during ischemia and early reperfusion in rats. Stroke 30:1279–85. |
| 49. | Toung TJ, Hurn PD, Bhardwaj A, Dawson VL, Dawson TM, Traystman RJ (1997) Immunosuppressive agent FK506 reduces experimental stroke injury. J Cereb Blood Flow Metab 17:S617–55. |
| 50. | Wardlaw JM, Keir SL, Bastin ME, Armitage PA, Rana AK (2002) Is diffusion imaging appearance an independent predictor of outcome after ischemic stroke? Neurology 59:1381–7. |
| 51. | Weinbrenner C, Liu GS, Downey JM, Cohen MV (1998) Cyclosporine A limits myocardial infarct size even when administered after onset of ischemia. Cardiovasc Res 38:678–84. |
| 52. | Yoshimoto T, Siesjo BK (1999) Posttreatment with the immunosuppressant cyclosporin A in transient focal ischemia. Brain Res 839:283–91. |
- 1. Aoyama S, Katayama Y, Terashi A (1997) The effect of FK 506, an immunosuppressant, on cerebral infarction volume in focal cerebral ischemia in rats. Nippon Ika Daigaku Zasshi—J Nippon Med School 64:416–21.
- 2. Arii T, Kamiya T, Arii K, Ueda M, Nito C, Katsura KI, Katayama Y (2001) Neuroprotective effect of immunosuppressant FK506 in transient focal ischemia in rat: therapeutic time window for FK506 in transient focal ischemia. Neurol Res 23:755–60.
- 3. Aronowski J, Grotta JC, Strong R, Waxham MN (2000) Interplay between the gamma isoform of PKC and calcineurin in regulation of vulnerability to focal cerebral ischemia. J Cereb Blood Flow Metab 20:343–9.
- 4. Bebarta V, Luyten D, Heard K (2003) Emergency medicine animal research: does use of randomization and blinding affect the results? Acad Emerg Med 10:684–7.
- 5. Bochelen D, Rudin M, Sauter A (1999) Calcineurin inhibitors FK506 and SDZ ASM 981 alleviate the outcome of focal cerebral ischemic/reperfusion injury. J Pharmacol Exp Ther 288:653–9.
- 6. Brecht S, Schwarze K, Waetzig V, Christner C, Heiland S, Fischer G, Sartor K, Herdegen T (2003) Changes inpeptidyl-prolyl cis/trans 7isomerase activity and FK506 binding protein expression following neuroprotection by FK506 in the ischemic rat brain. Neuroscience 120:1037–48.
- 7. Butcher SP, Henshall DC, Teramura Y, Iwasaki K, Sharkey J (1997) Neuroprotective actions of FK506 in experimental stroke: in vivo evidence against an antiexcitotoxic mechanism. J Neurosci 17:6939–46.
- 8. Chang ML, Yang J, Kem S, Klaidman L, Sugawara T, Chan PH, Adams Jr JD (2002) Nicotinamide and ketamine reduce infarct volume and DNA fragmentation in rats after brain ischemia and reperfusion. Neurosci Lett 322:137–40.
- 9. Chung SY, Lin JY, Lin MC, Liu HM, Wang MF, Cheng FC (2004) Synergistic efficacy of magnesium sulfate and FK506 on cerebral ischemia-induced infarct volume in gerbil. Med Sci Monit 10:BR105–8.
- 10. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–88.
- 11. Ebisu T, Katsuta K, Fujikawa A, Aoki I, Umeda M, Naruse S, Tanaka C (2001) Early and delayed neuroprotective effects of FK506 on experimental focal ischemia quantitatively assessed by diffusion-weighted MRI. Magn Reson Imaging 19:153–60.
- 12. Egger M, Davey Smith G, Altman DG (2001) Systematic Reviews in Health Care: Meta-analysis in Context. London: BMJ Books.
- 13. Engelter ST, Provenzale JM, Petrella JR, DeLong DM, Alberts MJ (2003) Infarct volume on apparent diffusion coefficient maps correlates with length of stay and outcome after middle cerebral artery stroke. Cerebrovasc Dis 15:188–91.
- 14. Fredduzzi S, Mariucci G, Tantucci M, Del Soldato P, Ambrosini MV (2001) Nitro-aspirin (NCX4016) reduces brain damage induced by focal cerebral ischemia in the rat. Neurosci Lett 302:121–4.
- 15. Furuichi Y, Katsuta K, Maeda M, Ueyama N, Moriguchi A, Matsuoka N, Goto T, Yanagihara T (2003a) Neuroprotective action of tacrolimus (FK506) in focal and global cerebral ischemia in rodents: dose dependency, therapeutic time window and long-term efficacy. Brain Res 965:137–45.
- 16. Furuichi Y, Maeda M, Moriguchi A, Sawamoto T, Kawamura A, Matsuoka N, Mutoh S, Yanagihara T (2003b) Tacrolimus, a potential neuroprotective agent, ameliorates ischemic brain damage and neurologic deficits after focal cerebral ischemia in nonhuman primates. J Cereb Blood Flow Metab 23:1183–94.
- 17. Horn J, de Haan RJ, Vermeulen M, Luiten PG, Limburg M (2001) Nimodipine in animal model experiments of focal cerebral ischemia: a systematic review. Stroke 32:2433–8.
- 18. Janelidze S, Yoshimoto T, Kristian T, Siesjo BK (1999) The role of strain differences on the efficacy of PBN (N-tertbutyl-phenylnitrone) and FK506 treatment in transient focal ischemia. J Cereb Blood Flow Metab 19(Suppl 1):S171.
- 19. Kuroda S, Janelidze S, Siesjo BK (1999) The immunosuppressants cyclosporin A and FK506 equally ameliorate brain damage due to 30-min middle cerebral artery occlusion in hyperglycemic rats. Brain Res 835:148–53.
- 20. Kuroda S, Siesjo BK (1996) Postischemic administration of FK506 reduces infarct volume following transient focal brain ischemia. Neurosci Res Commun 19:83–90.
- 21. Labiche LA, Grotta JC (2004) Clinical trials for cytoprotection in stroke. NeuroRx 1:46–70.
- 22. Liu J, Farmer Jr JD, Lane WS, Friedman J, Weissman I, Schreiber SL (1991) Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell 66:807–15.
- 23. Macleod MR, Allsopp TE, McLuckie J, Kelly JS (2001) Serum withdrawal causes apoptosis in SHSY 5Y cells. Brain Res 889:308–15.
- 24. Macleod MR, O’Collins T, Horky LL, Howells DW, Donnan GA (2005) Systematic review and meta-analysis of the efficacy of melatonin in experimental stroke. J Pineal Res 38:35–41.
- 25. Macleod MR, O’Collins T, Howells DW, Donnan GA (2004) Pooling of animal experimental data reveals influence of study design and publication bias. Stroke 35:1203–8.
- 26. Maeda M, Furuichi Y, Ueyama N, Moriguchi A, Satoh N, Matsuoka N, Goto T, Yanagihara T (2002) A combined treatment with tacrolimus (FK506) and recombinant tissue plasminogen activator for thrombotic focal cerebral ischemia in rats: increased neuroprotective efficacy and extended therapeutic time window. J Cereb Blood Flow Metab 22:1205–11.
- 27. Martin D, Lodge D (1985) Ketamine acts as a noncompetitive N-methyl-D-aspartate antagonist on frog spinal cord in vitro. Neuropharmacology 24:999–1003.
- 28. McCarter JF, McGregor AL, Jones PA, Sharkey J (2001) FK 506 protects brain tissue in animal models of stroke. Transplant Proc 33:2390–2.
- 29. McGregor AL, Marston HM, Sharkey J (2001) Reduced mortality and improved functional outcome associated with FK506 treatment in a mouse model of MCA occlusion. J Cereb Blood Flow Metab 21(Suppl 1):S244.
- 30. Miyazawa N, Saji H, Takaishi Y, Nukui H (2000) Protective effect of FK506 in the reperfusion model after shortterm occlusion of middle cerebral artery in the rat: assessment by autoradiography using [125I]PK-11195. Neurol Res 22:630–3.
- 31. Moher D, Schulz KF, Altman DG (2001) The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials. Lancet 357:1191–4.
- 32. Murphy GJ, Waller JR, Sandford RS, Furness PN, Nicholson ML (2003) Randomized clinical trial of the effect of microemulsion cyclosporin and tacrolimus on renal allograft fibrosis. Br J Surg 90:680–6.
- 33. Nalesnik MA, Lai HS, Murase N, Todo S, Starzl TE (1990) The effect of FK 506 and CyA on the Lewis rat renal ischemia model. Transplant Proc 22:87–9.
- 34. NINDS (2000) Effect of intravenous recombinant tissue plasminogen activator on ischemic stroke lesion size measured by computed tomography. Stroke 31:2912–9.
- 35. Nito C, Kamiya T, Ueda M, Amemiya S, Inaba T, Katayama Y (2002) Mild hypothermia enhances neuroprotective effects of immunosuppressant FK506 following transient focal ischemia in rats. Society for Neuroscience Abstract No 491.8.
- 36. Nito C, Kamiya T, Ueda M, Arii T, Katayama Y (2004) Mild hypothermia enhances the neuroprotective effects of FK506 and expands its therapeutic window following transient focal ischemia in rats. Brain Res 1008:179–85.
- 37. Pound P, Ebrahim S, Sandercock P, Bracken MB, Roberts I (2004) Where is the evidence that animal research benefits humans? BMJ 328:514–7.
- 38. Sharkey J, Butcher SP (1994) Immunophilins mediate the neuroprotective effects of FK506 in focal cerebral ischaemia. Nature 371:336–9.
- 39. Sharkey J, Crawford JH, Butcher SP, Marston HM (1996) Tacrolimus (FK506) ameliorates skilled motor deficits produced by middle cerebral artery occlusion in rats. Stroke 27:2282–6.
- 40. Sharkey J, Teramura Y, Iwasaki K, Butcher SP (1997) Brain levels of FK506 and neuroprotection in experimental stroke. Br J Pharmacol 122:329.
- 41. Shichinohe H, Kuroda S, Abumiya T, Ikeda J, Kobayashi T, Yoshimoto T, Iwasaki Y (2004) FK506 reduces infarct volume due to permanent focal cerebral ischemia by maintaining BAD turnover and inhibiting cytochrome c release. Brain Res 1001:51–9.
- 42. Stroke Academic Industry Roundtable (1999) Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 30:2752–8.
- 43. Suzuki S, Toledo-Pereyra LH, Rodriguez FJ, Cejalvo D (1993) Neutrophil infiltration as an important factor in liver ischemia and reperfusion injury. Modulating effects of FK506 and cyclosporine. Transplantation 55:1265–72.
- 44. Takamatsu H, Kondo K, Ikeda Y, Umemura K (1998) Neuroprotective effects depend on the model of focal ischemia following middle cerebral artery occlusion. Eur J Pharmacol 362:137–42.
- 45. Takamatsu H, Tsukada H, Noda A, Kakiuchi T, Nishiyama S, Nishimura S, Umemura K (2001) FK506 attenuates early ischemic neuronal death in a monkey model of stroke. J Nucl Med 42:1833–40.
- 46. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group (1995) Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 333:1581–8.
- 47. Tong DC, Yenari MA, Albers GW, O’Brien M, Marks MP, Moseley ME (1998) Correlation of perfusion- anddiffusion-weighted MRI with NIHSS score in acute (o6.5 hour) ischemic stroke. Neurology 50:864–70.
- 48. Toung TJ, Bhardwaj A, Dawson VL, Dawson TM, Traystman RJ, Hurn PD (1999) Neuroprotective FK506 does not alter in vivo nitric oxide production during ischemia and early reperfusion in rats. Stroke 30:1279–85.
- 49. Toung TJ, Hurn PD, Bhardwaj A, Dawson VL, Dawson TM, Traystman RJ (1997) Immunosuppressive agent FK506 reduces experimental stroke injury. J Cereb Blood Flow Metab 17:S617–55.
- 50. Wardlaw JM, Keir SL, Bastin ME, Armitage PA, Rana AK (2002) Is diffusion imaging appearance an independent predictor of outcome after ischemic stroke? Neurology 59:1381–7.
- 51. Weinbrenner C, Liu GS, Downey JM, Cohen MV (1998) Cyclosporine A limits myocardial infarct size even when administered after onset of ischemia. Cardiovasc Res 38:678–84.
- 52. Yoshimoto T, Siesjo BK (1999) Posttreatment with the immunosuppressant cyclosporin A in transient focal ischemia. Brain Res 839:283–91.