Journal Article

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

Gharaylou, Zeinab, Kebriaeezadeh, Abbas, Hadjighassem, Mahmoudreza, Aghamollaii, Vajihe, Agah, Elmira, Tafakhori, Abbas

2019

Overview

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.

• Publisher: Springer International Publishing,Springer Nature B.V
• Subject: Adult / Anorexia / Anticonvulsants - administration & dosage / Anticonvulsants - adverse effects / Anticonvulsants - therapeutic use / Antiepileptic agents / Bumetanide / Bumetanide - administration & dosage / Bumetanide - adverse effects / Bumetanide - therapeutic use / Chloride / Chloride transport / Clinical trials / Convulsions & seizures / Drug dosages / Drug resistance / Drug Resistant Epilepsy - drug therapy / Drug Therapy, Combination / Epilepsy / Female / Headache / Human subjects / Humans / Hypoxia / IRCT / IRCT 201012115368N1 / Male / Medicine / Medicine & Public Health / Nausea / Neurology / Neurosciences / Newborn babies / NMR / Nuclear magnetic resonance / Original Research Article / Patients / Pharmacotherapy / Pharmacovigilance / Polymerase chain reaction / Potassium-chloride cotransporter / Proteins / Psychiatry / Psychopharmacology / Safety / Seizures / Sodium Potassium Chloride Symporter Inhibitors - administration & dosage / Sodium Potassium Chloride Symporter Inhibitors - adverse effects / Sodium Potassium Chloride Symporter Inhibitors - therapeutic use / Solute Carrier Family 12, Member 2 - genetics / Solute Carrier Family 12, Member 2 - metabolism / Symporters - genetics / Symporters - metabolism / Temporal lobe / Titration / Transcription, Genetic - drug effects / Treatment Outcome / Vomiting / Young Adult