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A Preliminary Study Evaluating the Safety and Efficacy of Bumetanide, an NKCC1 Inhibitor, in Patients with Drug-Resistant Epilepsy

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A Correction to this article was published on 23 July 2019

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Abstract

Background

Dysregulation of cation-chloride cotransporters NKCC1 and KCC2 expression was shown to be related to drug-resistant epilepsy. Previous studies suggested that bumetanide, an inhibitor of NKCC1, might have antiepileptic effects.

Objective

The aim of this study was to investigate the safety and efficacy of bumetanide add-on therapy in patients with drug-resistant epilepsy and its relation to cation-chloride cotransporters NKCC1 and KCC2.

Methods

We conducted an open-label, single-arm clinical trial in drug-resistant temporal lobe epilepsy (TLE) patients. This study consisted of three phases: pretreatment (3 months), titration (3 weeks), and active treatment (6 months). During the pretreatment phase, the dose of antiepileptic drugs was stabilized, and bumetanide was then added at an initial dose of 0.5 mg/day, increasing by 0.5 mg/week until a target dose of 2 mg/day was achieved. Bumetanide treatment was then continued for 6 months. Seizure frequency and adverse events were assessed at every monthly visit. Blood samples were collected from patients and 12 healthy controls were used for polymerase chain reaction and Western blot analyses. Primary clinical outcomes were drug safety and change in seizure frequency. Changes in NKCC1 and KCC2 expression were the non-clinical endpoints.

Results

A total of 30 patients were enrolled, 27 of whom completed the study. The mean duration of epilepsy was 16.5 years. Median seizure frequency per month was 9 [interquartile range (IQR) 7–14.5] at baseline, 3.67 (IQR 1.84–6.17) at the first 3 months, and 2 (IQR 0.84–4.34) at the last 3 months (p < 0.001). Five adverse events were detected in six patients. The reported adverse events were anorexia in four patients, nausea and vomiting in two patients, and agitation, headache and increased seizure frequency in one patient each. The level of NKCC1 and KCC2 gene transcripts and KCC2 protein did not change significantly following treatment (p > 0.05); however, we observed a significant reduction in NKCC1 protein levels (p = 0.042).

Conclusions

Bumetanide might be an effective and relatively tolerable drug in patients with drug-resistant TLE. Downregulation of NKCC1 protein following bumetanide treatment may be responsible for its antiepileptic effects.

Iranian Registry of Clinical Trials Identifier

IRCT 201012115368N1.

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Change history

  • 23 July 2019

    The correct name of the co-author should be ‘‘Vajiheh Aghamollaii’’, and not ‘‘Vajihe Aghamollaii’’ as given in the original publication of the article.

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Author information

Authors and Affiliations

  1. Department of Neuroscience and Addiction Study, School of Advanced Technologies in Medicine, International Campus, Tehran University of Medical Sciences, Tehran, Iran

    Zeinab Gharaylou

  2. Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran

    Abbas Tafakhori

  3. Students’ Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran

    Elmira Agah

  4. NeuroImmunology Research Association (NIRA), Universal Scientific Education and Research Network (USERN), Tehran, Iran

    Elmira Agah

  5. Department of Neurology, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran

    Vajihe Aghamollaii

  6. Pharmaceutical Management and Economic Research Center, Tehran University of Medical Sciences, Tehran, Iran

    Abbas Kebriaeezadeh

  7. Department of Neuroscience and Addiction Study, School of Advanced Technologies in Medicine, International Campus, Tehran University of Medical Sciences, Tehran, Iran

    Mahmoudreza Hadjighassem

  8. Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran

    Mahmoudreza Hadjighassem

Authors
  1. Zeinab Gharaylou
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  2. Abbas Tafakhori
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  3. Elmira Agah
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  4. Vajihe Aghamollaii
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  5. Abbas Kebriaeezadeh
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  6. Mahmoudreza Hadjighassem
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Contributions

ZG: study design, data collection, data analysis, and manuscript writing; AT and VA: study design and data collection; EA: data analysis and manuscript writing; AK: data collection; MH: study idea, study design, and manuscript writing.

Corresponding author

Correspondence to Mahmoudreza Hadjighassem.

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Funding

No funding was received for this work.

Conflict of interest

Zeinab Gharaylou, Abbas Tafakhori, Elmira Agah, Vajihe Aghamollaii, Abbas Kebriaeezadeh and Mahmoudreza Hadjighassem declare that they have no competing interest.

Ethical approval

The Ethics Committee of Tehran University of Medical Sciences approved this study.

Patient consent

Informed consent was obtained from all study participants prior to commencement of this study.

Electronic Supplementary Material

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Gharaylou, Z., Tafakhori, A., Agah, E. et al. A Preliminary Study Evaluating the Safety and Efficacy of Bumetanide, an NKCC1 Inhibitor, in Patients with Drug-Resistant Epilepsy. CNS Drugs 33, 283–291 (2019). https://doi.org/10.1007/s40263-019-00607-5

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  • DOI: https://doi.org/10.1007/s40263-019-00607-5

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