Saturday, 1 April 2017

Yet more bumetanide and autism findings

Bumetanide, a loop diuretic medicine typically used to treat heart failure, is probably not something that most people would associate with 'attenuating' some of the presented characteristics of autism. This Na-K-Cl cotransporter (NKCC) blocking drug (influencing chloride concentrations in neurons and impacting on the actions of gamma-Aminobutyric acid, GABA) has however made quite a few appearances in the peer-reviewed autism research literature (see here and see here) and beyond (see here). The results of a further "multicenter phase 2B study primarily to assess dose/response and safety effects of bumetanide" in relation to autism [1] (open-access) add to the research in this area.

The names on this recent paper are familiar ones to the bumetanide-autism story as 'dose' and 'adverse effects' were the primary factors in this most recent gold-standard "double-blind, randomized, placebo-controlled, multisite dose-ranging study." Looking at some 88 participants diagnosed with an autism spectrum disorder (ASD) and "spanning across the entire pediatric population (2–18 years old)" various doses of [liquid] bumetanide or a placebo were given over 3 months. Assessments were carried out using various schedules including the Childhood Autism Rating Scale (CARS). As per the 'phase 2B' status of this research, the name of the game was optimising effective dosage of bumetanide against safety (side-effects) including gathering data on pharmacokinetics.

Results: "our results showed that bumetanide is safe but is associated with adverse events related to diuresis and dehydration." It's perhaps not surprising that a medicine classed as a loop diuretic does what it says on the tin. Authors describe various adverse effects - treatment emergent adverse events (TEAEs) - associated with bumetanide use: "The most frequent adverse events were hypokalemia, increased urine elimination, loss of appetite, dehydration and asthenia." Several participants withdrew from the study as a result of them.

Further: "The results of this dose-ranging study demonstrated the highest efficacy of bumetanide 2 mg twice a day on both primary and secondary end points." Various improvements were noted in the CARS and other scores as a consequence of the use of bumetanide (at various dosages): "23 bumetanide-treated and only one placebo showed more than six-point reduction in CARS from screening to day 90."  Marrying the safety (TEAEs) and effectiveness data (CARS et al) together, the authors concluded that: "bumetanide improves the core symptoms of ASD and presents a favorable benefit/risk ratio particularly at 1.0 mg twice daily."

I know for some any adverse effects from a 'treatment' option with autism in mind is going to be too much. I respect this view particularly in light of the medical tenet: first do no harm. But I don't think these latest results from Lemonnier and colleagues can just be ignored in terms of the potential hows-and-whys of response to bumetanide in relation to the presentation of autistic behaviours. Many (all) medications 'indicated' for the management of core or peripheral features associated with a diagnosis of autism have a risk profile attached to them (see here for example) but are still often quite widely used. This is not an excuse, just a statement of fact until someone, somewhere develops side-effect free versions of medicines in use. There is also another angle to this 'risk' profile to consider: "There was no simple relation between TEAEs and efficacy." What this tells us is that those 'best' responders to bumetanide were not necessarily the same participants who experienced adverse effects from the [active] medication; for example: "none of the moderate hypokalemic patients (<3 mm l−1) were high responder patients with at least 6 points in CARS change from screening to day 90." Sweeping generalisations are not required.

Where next for bumetanide?  Well, I don't doubt we will be hearing more from this group as they report: "this trial must be viewed as a source of data on the safety and dose-ranging usage of bumetanide and it provides further support to justify a large multisite European Phase III trial." Large, multi-centre trials are both expensive and take a considerable amount of planning so I'm not expecting to see anything too soon. But I don't think we've heard the last of bumetanide and autism...

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[1] Lemonnier E. et al. Effects of bumetanide on neurobehavioral function in children and adolescents with autism spectrum disorders. Translational Psychiatry. 2017; 7: e1056.

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ResearchBlogging.org Lemonnier, E., Villeneuve, N., Sonie, S., Serret, S., Rosier, A., Roue, M., Brosset, P., Viellard, M., Bernoux, D., Rondeau, S., Thummler, S., Ravel, D., & Ben-Ari, Y. (2017). Effects of bumetanide on neurobehavioral function in children and adolescents with autism spectrum disorders Translational Psychiatry, 7 (3) DOI: 10.1038/tp.2017.10