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ORIGINAL ARTICLE
Year : 2012  |  Volume : 60  |  Issue : 1  |  Page : 23-28

Efficacy of minocycline in acute ischemic stroke: A single-blinded, placebo-controlled trial


1 Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Neuroradiology, All India Institute of Medical Sciences, New Delhi, India

Date of Submission05-Sep-2011
Date of Decision28-Sep-2011
Date of Acceptance25-Dec-2011
Date of Web Publication7-Mar-2012

Correspondence Address:
M V Padma Srivastava
Department of Neurology, AIIMS, New Delhi
India
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Source of Support: None, Conflict of Interest: None


PMID: 22406775

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 » Abstract 

Background: Minocycline is a semisynthetic derivative of the tetracycline group of antibiotics, which have neuroprotective effects. In animal stroke models, minocycline had shown promising evidence to improve clinical and functional outcomes. Objective: To analyze the effect of oral minocycline in acute ischemic stroke patients. Materials and Methods: This was a randomized single-blinded open-label study. The study group received oral minocycline 200 mg/day for 5 days and the control group received oral vitamin B capsules. Baseline assessment included the following: National Institute of Health Stroke Scale (NIHSS) score, modified Barthel Index (mBI), modified Rankin Scale (mRS) score, Magnetic Resonance Imaging (MRI) of brain including Diffusion Weighted Imaging (DWI), chest X-ray, and routine laboratory investigations. The clinical scales were repeated at days 1, 7, and 30. The end point was outcomes at 3 months (90 days). Statistical analysis was done with SPSS 11.5 (P<0.05). Paired t-test and multiple-measures Analysis Of Variance (ANOVA) were used. Results: Fifty patients with acute ischemic stroke were included in the study. Of these, 23 patients received minocycline and 27 patients received placebo i.e., vitamin B capsules. NIHSS score in patients receiving minocycline had shown statistically significant improvement at day 30 and 90 as compared with the controls. Similarly, mRS scores and BI showed significant improvement in patients receiving minocycline at three months as compared to the control group. No mortality, myocardial infarctions, recurrent strokes, and hemorrhagic transformations were noted in both groups. Conclusions: Patients with acute ischemic stroke had significantly better outcome with minocycline treatment as compared with those administered placebo. The above findings suggest that minocycline can be helpful in reducing the clinical deficits after acute ischemic stroke.


Keywords: Acute ischemic stroke, functional impairment, minocycline, neuroprotection


How to cite this article:
Padma Srivastava M V, Bhasin A, Bhatia R, Garg A, Gaikwad S, Prasad K, Singh MB, Tripathi M. Efficacy of minocycline in acute ischemic stroke: A single-blinded, placebo-controlled trial. Neurol India 2012;60:23-8

How to cite this URL:
Padma Srivastava M V, Bhasin A, Bhatia R, Garg A, Gaikwad S, Prasad K, Singh MB, Tripathi M. Efficacy of minocycline in acute ischemic stroke: A single-blinded, placebo-controlled trial. Neurol India [serial online] 2012 [cited 2016 Aug 26];60:23-8. Available from: http://www.neurologyindia.com/text.asp?2012/60/1/23/93584



 » Introduction Top


Minocycline is the second-generation tetracycline derivative known to have anti-inflammatory effects independent of its antimicrobial action. Recent studies have shown that minocycline prevents microglial activation [1],[2],[3],[4],[5] and also has notable beneficial effects in animal models of global and transient focal cerebral ischemia [6],[7] and other brain injuries. [8],[9],[10] Although inhibition of a number of cellular targets, including caspase-1, [9],[4] caspase-3, [9] cyclo-oxygenase-2, [5] inducible nitric oxide synthase, [4],[5] p38 mitogen-activated protein kinase, [10],[1] Matrix Metalloproteinase (MMP)-9 [8] have been reported to be associated with neuroprotective effects of minocycline; however, the exact molecular targets of minocycline are yet to be identified. Cerebral ischemia triggers both extracellular and intracellular proteolytic cascades leading to breakdown of the Blood-Brain Barrier (BBB) and loss of microvascular integrity. [11],[12],[13] Vascular injury results in edema, activation of resident microglial cells, infiltration of circulating inflammatory cells into the brain and, finally, neuronal death. [14],[15] The proposed mechanisms of minocycline include anti-inflammatory effects, [4] reduction of microglial activation, MMP reduction, [5] nitric oxide production and inhibition of apoptotic cell death. A protective effect of minocycline has been demonstrated in spinal cord culture against N-methyl-D-aspartate excitotoxicity. [16] This drug is known to have significant effect on the apoptotic cell death and prevention of activated caspase-3 formation. [9] Recent studies have shown that inhibition of MMP-9 by genetic, immunologic, or pharmacologic approaches reduces infarct volumes in mice, thus suggesting a deleterious role of MMP-9 in ischemic brain injury. [17] In addition, expression of pro-MMP-2 is directly related to neuronal injury and its role in ischemic injury is supported by the findings that activation of pro-MMP-2 as well as its protease activity are triggered after brain ischemia. [18],[19] Some of the studies had not shown beneficial effects of minocycline and have reported that it was unsuccessful in preventing the mitochondrial swelling induced by malonate. [20],[21],[22]

The Global Burden of Disease (GBD) study reported 9.4 million deaths in India, of which 619,000 were from stroke, [23] with approximately 28.5 million Disability Adjusted Life Years (DALYs) lost due to the disease. Since less than 1% of patients have access to Recombinant Tissue Plasminogen Activator (rtPA) in the narrow therapeutic time window of 4½ hours, it is imperative to find a low-cost effective treatment with a longer therapeutic time window to be applicable to a larger number of patients. It in this regard, oral treatment with minocycline if proved effective will be of paramount importance. With the evidence in favor of a potential benefits of minocycline in acute ischemic stroke, the present study was designed with the specific objective of evaluating the efficacy of oral minocycline in patients with acute ischemic stroke in the Indian context. The hypothesis of the present study was that oral minocycline will aid in neuroprotection in acute ischemic stroke.


 » Materials and Methods Top


This was a single-blinded, placebo-controlled trial with a sample size of 50 patients suffering from acute ischemic stroke and was conducted at All India Institute of Medical Sciences (AIIMS), New Delhi. The inclusion criteria were as follows : patients with first-ever ischemic stroke with 6-24 hours of symptom onset, age >18 years and National Institute of Health Stroke Scale (NIHSS) [24] score of >4. Patients with the following conditions were excluded: hemorrhagic stroke, evidence of other diseases of the Central Nervous System (CNS) including brain tumor, demyelinating diseases, inflammatory diseases, craniotomies, severe brain injuries, idiopathic intracranial hypertension, known allergy to tetracycline group of drugs, acute, or chronic renal failure and pre-existing infectious disease requiring other antibiotic therapy. All patients had the following evaluation: NIHSS, [24] modified Barthel Index (Activities of Daily Living scale), [25] modified Rankin Scale (mRS), [26] brain Magnetic Resonance Imaging (MRI) using in 1.5-Tesla MRI with Diffusion Weighted Imaging (DWI), chest X-ray and routine laboratory investigations (complete blood count, erythrocyte sedimentation rate, blood glucose, lipid profile, serum homocysteine, and urinalysis). NIHSS, mRS, and mBI were repeated at days 1, 7, and 30. The end point was outcome at 3 months (90 day). MRI was also repeated at the end of one and three months. This study has the approval from the Institute Ethics Committee and informed consent was taken from the patients and all subjects were blinded to treatment. The study design is shown in [Figure 1].
Figure 1: Flow chart showing the study design

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Intervention

Patients were allocated to two groups using by block randomization method from statistics department. Patients in the experimental group received, in addition to, standard care, minocycline 200 mg capsule per day for five days orally or through the Ryle's tube if they had difficulty in swallowing. Patients randomized to the placebo/control group in addition to standard care, received vitamin B-complex capsule, which resembled minocycline capsule and was prescribed at the same dose.

Statistical analysis

Data were analyzed using SPSS statistical analysis software (SPSS Inc., Chicago, IL, 1999). Parametric and non-parametric tests were applied for data analysis depending on the variable to be studied. We used paired t test, two sample t test, repeated-measures Analysis Of Variance (ANOVA)/multiple comparison test for NIHSS and BI. Wilcoxon signed rank test was used for analysis of mRS scores.


 » Results Top


The minocycline-treated group included 23 patients with acute ischemic stroke with mean age of 52.7±15.3 year and male: female ratio of 13:10. Control group included 27 patients with acute ischemic stroke with mean age of 57±14.2 and male: female ratio of 18:9 [Table 1]. The mean time to treatment in minocycline group was 13.5 h and, in the control group, it was 11.99 h. Of the total cohort, 24 patients received treatment between 10 and 12 h, 10 between 19 and 21 h, 11 between 14 and 8 h, 5 between 22 and 24 h. It was observed that patients in control group used anti-hypertensives more than those in minocycline group (18 (65.2%) versus 8 (34.7%); P=0.04) [Table 1].
Table 1: Demographic and risk factors in stroke patients


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Kolmogorov-Smirnov test was applied to assess the normality of the data, and it was greater than P>0.5, suggesting that the data was nominal. Two sample t-test and Man-Whitney U test were applied for between-group analysis; it was found that NIHSS was statistically significant in the minocycline-treated group at day 30 and day 90 (P=0.05 and P= 0.043, respectively) [Figure 2]. In the minocycline-treated group, mRS and mBI were statistically significant at three-monthly follow-up with P=0.04 and P=0.05, respectively [Figure 3] and [Figure 4]a,b. A mean two-point decrease in the minocycline group was observed as compared to that in the placebo group [Figure 5]. Repeated-measures ANOVA was applied to both groups and the results were statistically significant, with F=0.001 for all scores, although no significant difference was observed between the baseline and day 1 (P>0.05) and between the baseline and day 7 (P>0.05). The MRI findings also showed no statistical significant difference in the infarct volume on day 30 between the two groups (data of the infarct volume not shown). There was no mortality, no lost to follow-up or dropouts throught our study. The T2 and DWI images both were analyzed to measure the change in lesion volume. But no significant change was observed in the MRI scans [Table 2] and [Table 3].
Figure 2: Mean NIHSS score between experimental/minocycline and control group

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Figure 3: Mean modified Barthel Index score between experimental/minocycline and control group

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Figure 4: (a) Percentage of scores of modified Rankin score (mRS) in experimental/minocycline group. (b) Percentage of scores of modified Rankin score (mRS) in control group

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Figure 5: Mean NIHSS point difference between experimental/minocycline and control group

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Table 2: NIHSS, mRS, and mBI in experimental/minocycline-treated group at baseline and days 7, 30, and 90

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Table 3: NIHSS, m RS, and BI in control/placebo-treated group at baseline and days 7, 30, and 90

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 » Discussion Top


The primary objective of this study was to study the efficacy of minocycline; the drug was observed to be beneficial in patients with acute ischemic stroke and was associated with better clinical and functional outcome. The recovery was observed at one and three months as compared to the early stage, ie, day 7 of stroke in the experimental group. In vivo studies suggest that apoptotic cell death was observed 20 minute after ischemia, peaking 24-48 hour later and persisting for 4 weeks. [27] Some studies have reported a direct relationship between the number of apoptotic cells and duration of ischemia. [28] The first human trial was performed as an open-label, evaluator-blinded study. [29] Minocycline was administered at a dosage of 200 mg orally for 5 days in a therapeutic window time of 6-24 hour after the onset of stroke. The data evaluated included NIHSS score, mRS, and mBI. Of the 154 patients included in the study, 74 received minocycline. NIHSS scores and mRS were significantly lower and mBI scores were significantly higher in minocycline-treated patients. This pattern was apparent on day 7 and day 30 of follow-up. Our study also showed similar results; NIHSS score was significantly lower at day 30 and day 90; mRS was lower at day 90; moreover, a high BI at three-month follow-up indicating anti-apoptotic effect of minocycline. [30] We did not observe deaths, myocardial infarctions, recurrent strokes, and hemorrhagic transformations during follow-up in both the groups, thereby indicating tolerance of the drug at the prescribed dosage. Patients were screened for any prior infections before recruitment for the study and no post-stroke complications were observed. Recovery in stroke is explained by internal spontaneous events within first weeks to months after an insult, which might have altered the outcome measures. Since the patients did not differ in their baseline characteristics, we postulate that the favorable outcome measures would not have occurred by chance and must have been due to the drug administered.

We also acknowledge the limitations of the study: a small sample size, unblinded nature of the study, treatment window period of 6-24 hours, no stroke sub-typing classification, minocycline dosage, and oral delivery rather than intravenous delivery. Moreover, we did not calculate the levels of magnesium as part of routine laboratory investigations, which could have drug interactions with minocycline and may have altered the results.

Several clinical trials found minocycline treatment effective in reducing clinical deficits in Parkinson disease, [31] amyotrophic lateral sclerosis, [32] and multiple sclerosis. [33] Animal models provide promising evidence of minocycline's ability to improve outcomes in an animal stroke model. It has been validated that on a global brain ischemia model, pyramidal neuron survival increased from 10.5% to 77% after administration of minocycline. This result was probably attributable to a complete prevention of microglia ischemia-induced activation evidenced by the appearance of NADPHdiaphorese reactive cells. [6] It has also been reported that minocycline and other tetracyclines inhibited Poly [ADP-Ribose] Polymerase (PARP)-1 at nanomolar concentrations, while minocycline protected neurons against PARP-1-mediated toxicity. Other minocycline effects include inhibition of mitochondrial peripheral benzodiazepine receptor (recently renamed 18 kDa translocator protein), increased phosphorylation, membranal insertion of glutamate receptor 1, and inhibition of mitogen-activated protein kinases. [34] Minocycline administration 48 hour post-injury was found to significantly reduce the infarct volume in the focal embolic cerebral ischemia model and in reperfusion of the middle cerebral artery occlusion. [6],[7]

Minocycline treatment can be combined with other drug regimes with the hope of enhancing the beneficial effects without increasing the risk of adverse effects. This therapeutic strategy has already been approved useful in preliminary studies of many diseases. In developed countries, given the limited resources available for hospital treatments, [35] it would be logical to place greater emphasis on effective interventions to control or reduce the impairments and clinical deficits after stroke. The practical utility of the neuroprotective effects of minocycline, though based on a substantial body of promising in vitro and animal studies, continues to be a matter of intense debate, with contradictory evidence ranging from neuroprotection to the exacerbation of toxicity in various experimental models and human trials.

 
 » References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]

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