NKCC1 Inhibitor Bumetanide Shows No Effect on Parkinson Disease Progression

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The randomized, double-blind, placebo-controlled trial failed to show any beneficial symptomatic effect of 4-month treatment with 1.75–3.5 mg/day bumetanide on Parkinson disease.

Philippe Damier, MD, PhD, a professor of neurology at the Nantes University Hospital Center

Philippe Damier, MD, PhD

Data from a recently published 4-month trial (NCT03899324) showed that the use of bumetanide, an Na-K-CI contransporter (NKCC1) inhibitor, as an adjunct to levodopa, failed to improve motor symptoms in patients with Parkinson disease (PD). Despite the negative results, investigators concluded that future research should not completely exclude other agents that act on NKCC1, either with better brain penetration or with better tolerability, to improve PD symptoms.1

Published in Movement Disorders, the study included 44 patients with PD, aged 40 to 80 years old, who received either 1.75 to 3 mg/day of bumetanide or placebo. Patients underwent a 1-month dose adjustment period, followed by a 3-month treatment period, and a 1-month washout. At the conclusion of the 4-month period, the mean chance in OFF Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS)-III score was –3.0 (SD, 7.5) for bumetanide and –1.7 (SD, 6.6) for placebo (intent-to-treat [ITT], P = .78; PP analysis, P = .48).

Led by Philippe Damier, MD, PhD, a professor of neurology at the Nantes University Hospital Center, there was also a significant worsening of the MDS-UPDRS Part IB score in the bumetanide group (mean change, 3.1 [SD, 2.7]) compared with placebo (mean change, –0.3 [SD, 3.5]; P <.02 in per protocol [PP]). Investigators recorded no differences between the 2 groups for any of the other secondary, which included ON MDS-UPDRS motor score, other MDS-UPDRS scores, the collection of adverse events (AEs), a stand-walk-sit test, and the Giladi’s gait questionnaire.

The idea behind studying bumetanide is related to its mechanism of action and involvement with y-aminobutyric acid (GABA). In previous trials, bumetanide, a well-known loop diuretic, has been shown to inhibit NKCC1, ultimately regulating chloride levels in striatal neurons and thereby restoring GABAergic inhibition and thus the classical OFF response evoked by cortical stimulation. These observations raised the possibility that bumetanide might attenuate the severity of PD.

Between the active and placebo groups, there were no differences in exploratory outcomes as well, which included the unified dyskinesia rating scale score, the patient’s diary records, and the patient’s clinical global impression score at baseline, and after 30, 60, and 120 days of study drug treatment. Kalemia was assessed at each visit and at 1, 2, and 3 weeks after the inclusion; potassium was supplemented if kalemia was less than 3.5 mEq/l.

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In addition to failing to demonstrate efficacy, bumetanide also demonstrated a worse safety profile, with frequent AEs. Of the 44 participants, 39 experienced at least 1 AEs (bumetanide: n = 22 vs placebo: n = 17) and 27 with AEs were considered to be related to the study treatment (bumetanide: n = 20; placebo: n = 7). Urinary disorders, representing 19% of all AEs recorded, were the most frequently observed AE throughout the study. Of these, pollakiuria was observed in 61% of reported cases.

Among the 6 serious AEs observed in the trial (3 in each group), only 1 (coronary syndrome) was considered to be possibly linked to bumetanide treatment. Overall, the power of the study was decreased because of the large dropout rate. Of the 44 patients included, 14 withdrew prematurely from the study (bumetanide: n = 10; placebo: n = 4) and 6 elected to drop out during the course of the study. Notably, 8 patients were withdrawn by their local investigator, with AEs (n = 6) and physician decision (n = 2) as the reasons behind the move.

REFERENCE
1. Damier P, Degos B, Castelonovo G, et al. A double-blind, randomized, placebo-controlled trial of bumetanide in Parkinson’s disease. Mov Disord. 2024;39(3):618-622. doi:10.1002/mds.29726
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