Bumetanide is a selective NKCC1 chloride importer antagonist which is being repurposed as a mechanism-based treatment for neurodevelopmental disorders (NDDs). Due to their specific actions, these kinds of interventions will only be effective in particular subsets of patients. To anticipate stratified application, we recently completed three bumetanide trials each focusing on different stratification strategies with the additional objective of deriving the most optimal endpoints. Here we publish the protocol of the post-trial access combined cohort study to confirm previous effects and stratification strategies in the trial cohorts and in new participants.
Participants of the three previous cohorts and a new cohort will be subjected to 6 months bumetanide treatment using multiple baseline Single Case Experimental Designs. The primary outcome is the change, relative to baseline, in a set of patient reported outcome measures focused on direct and indirect effects of sensory processing difficulties. Secondary outcome measures include the conventional questionnaires \'social responsiveness scale\', \'repetitive behavior scale\', \'sensory profile\' and \'aberrant behavior scale\'. Resting-state EEG measurements will be performed at several time-points including at Tmax after the first administration. Assessment of cognitive endpoints will be conducted using the novel Emma Tool box, an in-house designed battery of computerized tests to measure neurocognitive functions in children.
This study aims to replicate previously shown effects of bumetanide in NDD subpopulations, validate a recently proposed treatment prediction effect methodology and refine endpoint measurements.
EudraCT: 2020-002196-35, registered 16 November 2020, https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-002196-35/NL.

The behavioral phenotypes emerge from cognitive architecture comprising attention, executive functions, and primary communication skills that all have shown remarkable deficits in Down\'s Syndrome (DS). These states arise from the proper functional interactions of the contributing neurotransmission and neuromodulation systems and other coding platforms. Gamma-aminobutyric acid (GABA) is an integral part of the neural interaction and regulation networks that its reverse action leads to broad detrimental consequences. This inhibitory substance needs an appropriate balance of co-transporters that largely shape the ionic milieu. Bumetanide, a specific NKCC1 inhibitor used for an eighteen-month interval, showed promising effects in restoring some behavior deficits in a fourteen-year-old boy diagnosed with genetically confirmed mosaic Down\'s Syndrome.

BACKGROUND: Bumetanide can induce generalized musculoskeletal pain when administered as a continuous infusion, an effect that may be underrecognized. The purpose of this case series is to educate health care providers about the incidence and presentation of pain associated with bumetanide infusions, adding to the existing literature describing this adverse event.
RESULTS: Of 40 critically ill patients, 15 (38%) had increased pain scores after initiation of a continuous infusion of bumetanide, with symptoms commonly occurring 12 to 24 hours after initiation of the infusion. Reported descriptions of the pain included generalized aching, soreness, burning, allodynia, headaches, and exacerbation of underlying pain in localized areas. Increases in patient-reported pain correlated directly with initiation of the continuous infusion of bumetanide.
METHODS: Four of the 15 bumetanide-associated pain events (27%) were recognized as such by the health care team.
METHODS: Bumetanide was promptly discontinued in the 4 identified cases. The 11 patients (73%) whose pain was not recognized as related to bumetanide remained on a continuous infusion of bumetanide and received pain medications including opioids. Infusions were stopped when patients transitioned to dialysis (n = 8 [53%]), began receiving comfort care (n = 5 [33%]), or completed diuresis therapy (n = 2 [13%]).
RESULTS: For all patients, pain symptoms resolved within 24 to 48 hours after discontinuation of bumetanide infusion with no significant electrolyte abnormalities.
CONCLUSIONS: Bumetanide-induced pain is more common than previously described. Early recognition of this adverse event can prevent patient discomfort and escalation of treatment.

BACKGROUND: Autism spectrum disorder (ASD) is a common neurodevelopmental disorder caused by complex interactions between genetic and environmental factors. Recent studies suggest that Vitamin D3 or bumetanide therapy may improve the core symptoms of ASD in some individuals. However, there are no guidelines that provide clinicians with evidence-based treatment regimens for the use of these therapies in ASD.
METHODS: A 30-month-old female was referred to our department because she did not respond when her name was called.
METHODS: The patient was diagnosed with ASD by a team of autism experts according to American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria.
METHODS: The patient was administered Vitamin D3 150,000 IU intramuscularly once a month and Vitamin D3 800 IU orally each day. After 6 months, Vitamin D3 supplementation was discontinued because of lack of effectiveness. Subsequently, oral bumetanide 0.5 mg twice daily was initiated.
RESULTS: The patient\'s symptoms remained unchanged after 6 months of Vitamin D3 supplementation, and her serum 25 (OH) D levels had reached 52.4 ng/mL. At the parent\'s request, Vitamin D3 supplementation was discontinued because of lack of effectiveness. Thereafter, bumetanide was initiated. After 1 month of bumetanide, the patient\'s Childhood Autism Rating Scale score was 26, which is below the cutoff score for ASD. This case report suggests that Vitamin D3 and bumetanide target different mechanisms in the pathogenesis of ASD.
CONCLUSIONS: Based on these observations, we discuss three possible scenarios for Vitamin D3 supplementation and propose that bumetanide should be initiated if Vitamin D3 supplementation is ineffective (identifier ChiCTR-CCC-13004498).

Administration of the diuretic and NKCC1 chloride cotransporter antagonist bumetanide reduces the severity of autism spectrum disorders in children, and this effect is mediated by a reduction of the elevated intracellular chloride concentrations and a reinforcement of GABAergic inhibition (Lemonnier et al Transl Psychiatry. 2012;2:e202; Tyzio et al Science. 2014;343:675-679). Here, we report that this treatment also reduces the severity of symptoms in an adolescent with schizophrenia. Long-term treatment reduced hallucinations significantly, suggesting that this treatment may also be useful to treat schizophrenia. Further clinical trials and experimental studies are warranted to test this hypothesis.

We report that daily administration of the diuretic NKCC1 chloride co-transporter, bumetanide, reduces the severity of autism in a 10-year-old Fragile X boy using CARS, ADOS, ABC, RDEG and RRB before and after treatment. In keeping with extensive clinical use of this diuretic, the only side effect was a small hypokalaemia. A double-blind clinical trial is warranted to test the efficacy of bumetanide in FRX.
CONCLUSIONS: This single case report showed an improvement of the scores of each test used after 3 months of treatment. Double-blind clinical trials are warranted to test the efficacy of bumetanide in FRX.

We present a case of sotalol-induced prolongation of the QT-interval with torsades de pointes in an octogenarian who was hospitalized because of gastroenteritis causing prerenal acute renal failure. Subsequent accumulation of sotalol caused a severe prolongation of the QT-interval on the surface ECG and ultimately torsades de pointes with loss of consciousness. The patient was successfully treated with temporary cardiac pacing, intravenous magnesium sulfate and definitive withdrawal of sotalol. The electrophysiological basis of the pro-arrhythmic properties of sotalol is reviewed in brief, additional risk factors are identified and treatment is outlined.

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