Skip to main content

Advertisement

SpringerLink
Log in

Minocycline for acute stroke treatment: a systematic review and meta-analysis of randomized clinical trials

  • Original Communication
  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

Background

Various randomized-controlled clinical trials (RCTs) have investigated the neuroprotective role of minocycline in acute ischemic stroke (AIS) or acute intracerebral hemorrhage (ICH) patients. We sought to consolidate and investigate the efficacy and safety of minocycline in patients with acute stroke.

Methods

Literature search spanned through November 30, 2017 across major databases to identify all RCTs that reported following efficacy outcomes among acute stroke patients treated with minocycline vs. placebo: National Institute of Health Stroke Scale (NIHSS), Barthel Index (BI), and modified Rankin Scale (mRS) scores. Additional safety, neuroimaging and biochemical endpoints were extracted. We pooled mean differences (MD) and risk ratios (RR) from RCTs using random-effects models.

Results

We identified 7 RCTs comprising a total of 426 patients. Of these, additional unpublished data was obtained on contacting corresponding authors of 5 RCTs. In pooled analysis, minocycline demonstrated a favorable trend towards 3-month functional independence (mRS-scores of 0–2) (RR = 1.31; 95% CI 0.98–1.74, p = 0.06) and 3-month BI (MD = 6.92; 95% CI − 0.92, 14.75; p = 0.08). In AIS subgroup, minocycline was associated with higher rates of 3-month mRS-scores of 0–2 (RR = 1.59; 95% CI 1.19–2.12, p = 0.002; I2 = 58%) and 3-month BI (MD = 12.37; 95% CI 5.60, 19.14, p = 0.0003; I2 = 47%), whereas reduced the 3-month NIHSS (MD − 2.84; 95% CI − 5.55, − 0.13; p = 0.04; I2 = 86%). Minocycline administration was not associated with an increased risk of mortality, recurrent stroke, myocardial infarction and hemorrhagic conversion.

Conclusions

Although data is limited, minocycline demonstrated efficacy and seems a promising neuroprotective agent in acute stroke patients, especially in AIS subgroup. Further RCTs are needed to evaluate the efficacy and safety of minocycline among ICH patients.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Zhu S, Stavrovskaya IG, Drozda M, Kim BY, Ona V, Li M, Sarang S, Liu AS, Hartley DM, Wu DC, Gullans S, Ferrante RJ, Przedborski S, Kristal BS, Friedlander RM (2002) Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature 417(6884):74–78. https://doi.org/10.1038/417074a

    Article  PubMed  CAS  Google Scholar 

  2. Popovic N, Schubart A, Goetz BD, Zhang SC, Linington C, Duncan ID (2002) Inhibition of autoimmune encephalomyelitis by a tetracycline. Ann Neurol 51(2):215–223

    Article  PubMed  CAS  Google Scholar 

  3. Brundula V, Rewcastle NB, Metz LM, Bernard CC, Yong VW (2002) Targeting leukocyte MMPs and transmigration: minocycline as a potential therapy for multiple sclerosis. Brain: J Neurol 125(Pt 6):1297–1308

    Article  Google Scholar 

  4. Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S, Bian J, Guo L, Farrell LA, Hersch SM, Hobbs W, Vonsattel JP, Cha JH, Friedlander RM (2000) Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nature Med 6(7):797–801. https://doi.org/10.1038/77528

    Article  PubMed  CAS  Google Scholar 

  5. Fan X, Lo EH, Wang X (2013) Effects of minocycline plus tissue plasminogen activator combination therapy after focal embolic stroke in type 1 diabetic rats. Stroke; J Cereb Circ 44(3):745–752. https://doi.org/10.1161/strokeaha.111.000309

    Article  CAS  Google Scholar 

  6. Soliman S, Ishrat T, Fouda AY, Patel A, Pillai B, Fagan SC (2015) Sequential therapy with minocycline and candesartan improves long-term recovery after experimental stroke. Transl Stroke Res 6(4):309–322. https://doi.org/10.1007/s12975-015-0408-8

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Machado LS, Sazonova IY, Kozak A, Wiley DC, El-Remessy AB, Ergul A, Hess DC, Waller JL, Fagan SC (2009) Minocycline and tissue-type plasminogen activator for stroke: assessment of interaction potential. Stroke 40(9):3028–3033. https://doi.org/10.1161/strokeaha.109.556852

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Murata Y, Rosell A, Scannevin RH, Rhodes KJ, Wang X, Lo EH (2008) Extension of the thrombolytic time window with minocycline in experimental stroke. Stroke 39(12):3372–3377. https://doi.org/10.1161/strokeaha.108.514026

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Kohler E, Prentice DA, Bates TR, Hankey GJ, Claxton A, van Heerden J, Blacker D (2013) Intravenous minocycline in acute stroke: a randomized, controlled pilot study and meta-analysis. Stroke 44(9):2493–2499. https://doi.org/10.1161/strokeaha.113.000780

    Article  PubMed  CAS  Google Scholar 

  10. Chang JJ, Kim-Tenser M, Emanuel BA, Jones GM, Chapple K, Alikhani A, Sanossian N, Mack WJ, Tsivgoulis G, Alexandrov AV, Pourmotabbed T (2017) Minocycline and matrix metalloproteinase inhibition in acute intracerebral hemorrhage: a pilot study. Eur J Neurol 24(11):1384–1391. https://doi.org/10.1111/ene.13403

    Article  PubMed  CAS  Google Scholar 

  11. Fouda AY, Newsome AS, Spellicy S, Waller JL, Zhi W, Hess DC, Ergul A, Edwards DJ, Fagan SC, Switzer JA (2017) Minocycline in acute cerebral hemorrhage: an early phase randomized trial. Stroke 48(10):2885–2887. https://doi.org/10.1161/strokeaha.117.018658

    Article  PubMed  CAS  Google Scholar 

  12. Blacker DJ, Prentice D, Alvaro A, Bates TR, Bynevelt M, Kelly A, Kho LK, Kohler E, Hankey GJ, Thompson A, Major T (2013) Reducing haemorrhagic transformation after thrombolysis for stroke: a strategy utilising minocycline. Stroke Res Treat 2013:362961. https://doi.org/10.1155/2013/362961

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Amiri-Nikpour MR, Nazarbaghi S, Hamdi-Holasou M, Rezaei Y (2015) An open-label evaluator-blinded clinical study of minocycline neuroprotection in ischemic stroke: gender-dependent effect. Acta Neurol Scand 131(1):45–50. https://doi.org/10.1111/ane.12296

    Article  PubMed  CAS  Google Scholar 

  14. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188

    Article  PubMed  CAS  Google Scholar 

  15. Sweeting MJ, Sutton AJ, Lambert PC (2004) What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. Stat Med 23(9):1351–1375. https://doi.org/10.1002/sim.1761

    Article  PubMed  Google Scholar 

  16. Higgins JP, Green S (2011) Cochrane handbook for systematic reviews of interventions, vol 4. Wiley, Chichester

    Google Scholar 

  17. Sterne JAC, Sutton AJ, Ioannidis JPA, Terrin N, Jones DR, Lau J, Carpenter J, Rücker G, Harbord RM, Schmid CH, Tetzlaff J, Deeks JJ, Peters J, Macaskill P, Schwarzer G, Duval S, Altman DG, Moher D, Higgins JPT (2011) Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ. https://doi.org/10.1136/bmj.d4002

    Article  PubMed Central  PubMed  Google Scholar 

  18. Sterne JA, Gavaghan D, Egger M (2000) Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. J Clin Epidemiol 53(11):1119–1129

    Article  PubMed  CAS  Google Scholar 

  19. Switzer JA, Hess DC, Ergul A, Waller JL, Machado LS, Portik-Dobos V, Pettigrew LC, Clark WM, Fagan SC (2011) Matrix metalloproteinase-9 in an exploratory trial of intravenous minocycline for acute ischemic stroke. Stroke 42(9):2633–2635. https://doi.org/10.1161/strokeaha.111.618215

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Fagan SC, Waller JL, Nichols FT, Edwards DJ, Pettigrew LC, Clark WM, Hall CE, Switzer JA, Ergul A, Hess DC (2010) Minocycline to improve neurologic outcome in stroke (MINOS): a dose-finding study. Stroke 41(10):2283–2287. https://doi.org/10.1161/strokeaha.110.582601

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Lampl Y, Boaz M, Gilad R, Lorberboym M, Dabby R, Rapoport A, Anca-Hershkowitz M, Sadeh M (2007) Minocycline treatment in acute stroke: an open-label, evaluator-blinded study. Neurology 69(14):1404–1410. https://doi.org/10.1212/01.wnl.0000277487.04281.db

    Article  PubMed  CAS  Google Scholar 

  22. Padma Srivastava MV, Bhasin A, Bhatia R, Garg A, Gaikwad S, Prasad K, Singh MB, Tripathi M (2012) Efficacy of minocycline in acute ischemic stroke: a single-blinded, placebo-controlled trial. Neurol India 60(1):23–28

    Article  PubMed  CAS  Google Scholar 

  23. Barr TL, Latour LL, Lee KY, Schaewe TJ, Luby M, Chang GS, El-Zammar Z, Alam S, Hallenbeck JM, Kidwell CS, Warach S (2010) Blood-brain barrier disruption in humans is independently associated with increased matrix metalloproteinase-9. Stroke 41(3):e123–e128. https://doi.org/10.1161/strokeaha.109.570515

    Article  Google Scholar 

  24. Li N, Liu YF, Ma L, Worthmann H, Wang YL, Wang YJ, Gao YP, Raab P, Dengler R, Weissenborn K, Zhao XQ (2013) Association of molecular markers with perihematomal edema and clinical outcome in intracerebral hemorrhage. Stroke 44(3):658–663. https://doi.org/10.1161/strokeaha.112.673590

    Article  PubMed  CAS  Google Scholar 

  25. Castellazzi M, Tamborino C, De Santis G, Garofano F, Lupato A, Ramponi V, Trentini A, Casetta I, Bellini T, Fainardi E (2010) Timing of serum active MMP-9 and MMP-2 levels in acute and subacute phases after spontaneous intracerebral hemorrhage. Acta Neurochir Suppl 106:137–140. https://doi.org/10.1007/978-3-211-98811-4_24

    Article  PubMed  Google Scholar 

  26. Alvarez-Sabin J, Delgado P, Abilleira S, Molina CA, Arenillas J, Ribo M, Santamarina E, Quintana M, Monasterio J, Montaner J (2004) Temporal profile of matrix metalloproteinases and their inhibitors after spontaneous intracerebral hemorrhage: relationship to clinical and radiological outcome. Stroke 35(6):1316–1322. https://doi.org/10.1161/01.str.0000126827.69286.90

    Article  PubMed  CAS  Google Scholar 

  27. Wu J, Yang S, Hua Y, Liu W, Keep RF, Xi G (2010) Minocycline attenuates brain edema, brain atrophy and neurological deficits after intracerebral hemorrhage. Acta Neurochir Suppl 106:147–150. https://doi.org/10.1007/978-3-211-98811-4_26

    Article  PubMed  CAS  Google Scholar 

Download references

Funding

This study received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Department of Neurology, Charleston Area Medical Center, West Virginia University-Charleston Division, Charleston, WV, 25301, USA

    Konark Malhotra

  2. Department of Critical Care Medicine, MedStar Washington Hospital Center, Washington, DC, USA

    Jason J. Chang

  3. Department of Hematology and Oncology, Cleveland Clinic Foundation, Cleveland, OH, USA

    Arjun Khunger

  4. Department of Neurology and Clinical Neurophysiology, Sir Charles Gairdner Hospital, Nedlands, WA, Australia

    David Blacker

  5. Department of Neurology, Medical College of Georgia at Augusta University, Georgia, USA

    Jeffrey A. Switzer

  6. Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, USA

    Nitin Goyal, Andrei V. Alexandrov & Georgios Tsivgoulis

  7. University of Connecticut/Hartford Hospital Evidence-based Practice Center, Hartford, CT, USA

    Adrian V. Hernandez

  8. School of Medicine, Universidad Peruana de Ciencias Aplicadas (UPC), Lima, Peru

    Adrian V. Hernandez

  9. ProEd Communications Inc., Cleveland, OH, USA

    Vinay Pasupuleti

  10. Second Department of Neurology, National and Kapodistrian University of Athens, “Attikon” University Hospital, Athens, Greece

    Georgios Tsivgoulis

Authors
  1. Konark Malhotra
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jason J. Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arjun Khunger
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David Blacker
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jeffrey A. Switzer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nitin Goyal
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Adrian V. Hernandez
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Vinay Pasupuleti
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Andrei V. Alexandrov
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Georgios Tsivgoulis
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

KM: Study concept and design, acquisition of data, analysis and interpretation, critical revision of the manuscript for important intellectual content. JJC: Acquisition and interpretation of data, critical revision of the manuscript for important intellectual content. AK: Analysis and interpretation, critical revision of the manuscript for important intellectual content. DB: Acquisition and interpretation of data, critical revision of the manuscript for important intellectual content. JAS: Acquisition and interpretation of data, critical revision of the manuscript for important intellectual content. NG: Acquisition and interpretation of data, critical revision of the manuscript for important intellectual content. AVH: Analysis and interpretation, critical revision of the manuscript for important intellectual content. VP: Analysis and interpretation, critical revision of the manuscript for important intellectual content. AVA: Acquisition and interpretation of data, critical revision of the manuscript for important intellectual content. GT: Study concept and design, study supervision, critical revision of the manuscript for important intellectual content.

Corresponding author

Correspondence to Konark Malhotra.

Ethics declarations

Conflicts of interest

Dr. Malhotra reports no disclosures. Dr. Chang reports no disclosures. Dr. Khunger reports no disclosures. Dr. Blacker reports no disclosures. Dr. Switzer reports no disclosures. Dr. Goyal reports no disclosures. Dr. Hernandez reports no disclosures. Dr. Pasupuleti reports no disclosures. Dr. Alexandrov reports no disclosures. Dr. Tsivgoulis reports no disclosures.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 844 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Malhotra, K., Chang, J.J., Khunger, A. et al. Minocycline for acute stroke treatment: a systematic review and meta-analysis of randomized clinical trials. J Neurol 265, 1871–1879 (2018). https://doi.org/10.1007/s00415-018-8935-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-018-8935-3

Keywords

Search

Navigation