Loop diuretics are open-channel blockers of the cystic fibrosis transmembrane conductance regulator with distinct kinetics

BACKGROUND AND PURPOSE

Loop diuretics are widely used to inhibit the Na⁺, K⁺, 2Cl⁻ co-transporter, but they also inhibit the cystic fibrosis transmembrane conductance regulator (CFTR) Cl⁻ channel. Here, we investigated the mechanism of CFTR inhibition by loop diuretics and explored the effects of chemical structure on channel blockade.

EXPERIMENTAL APPROACH

Using the patch-clamp technique, we tested the effects of bumetanide, furosemide, piretanide and xipamide on recombinant wild-type human CFTR.

KEY RESULTS

When added to the intracellular solution, loop diuretics inhibited CFTR Cl⁻ currents with potency approaching that of glibenclamide, a widely used CFTR blocker with some structural similarity to loop diuretics. To begin to study the kinetics of channel blockade, we examined the time dependence of macroscopic current inhibition following a hyperpolarizing voltage step. Like glibenclamide, piretanide blockade of CFTR was time and voltage dependent. By contrast, furosemide blockade was voltage dependent, but time independent. Consistent with these data, furosemide blocked individual CFTR Cl⁻ channels with ‘very fast’ speed and drug-induced blocking events overlapped brief channel closures, whereas piretanide inhibited individual channels with ‘intermediate’ speed and drug-induced blocking events were distinct from channel closures.

CONCLUSIONS AND IMPLICATIONS

Structure–activity analysis of the loop diuretics suggests that the phenoxy group present in bumetanide and piretanide, but absent in furosemide and xipamide, might account for the different kinetics of channel block by locking loop diuretics within the intracellular vestibule of the CFTR pore. We conclude that loop diuretics are open-channel blockers of CFTR with distinct kinetics, affected by molecular dimensions and lipophilicity.     

Predictors of upper limb spasticity after stroke? A systematic review and meta-analysis

ObjectiveTo determine the predictive markers for the occurrence of upper limb spasticity in the first 12 months after stroke.Data sourcesA systematic review was undertaken of the databases MEDLINE, EMBASE, CINAHL and PEDRO to 31st December 2017.Study selectionNon-experimental or experimental studies that included a control group with spasticity who did not receive an experimental intervention which investigated at least one variable (explanatory variable) measured at baseline against the development (or not) of spasticity at a future time point within 12 months post stroke were selected independently by two reviewers. Eleven papers met the selection criteria.Study appraisalData were extracted into tabular format using predefined data fields by two reviewers. Study quality was evaluated using the modified Downs and Black tool. Data were analysed using a meta-analysis or narrative review.ResultsTen studies, including 856 participants were analysed. The predictive markers of upper limb spasticity at one month post stroke were: motor 11.25 (odds ratio, OR); [95% CI:2.48, 51.04] and sensory impairments 4.91 (OR); [1.24, 19.46]; haemorrhagic stroke 3.70 (OR); [1.05, 12.98] and age 0.01 (OR) [0.00, 69.89]. Only motor impairment was found as a significant predictor at six months post stroke 30.68 (OR); [1.60, 587.06].LimitationsLow number of studies exploring biomechanical and neurophysiological in addition to behavioural predictors of spasticity were included.Conclusion and implications of key findingsUsing the results, the identified predictive markers have potential to better inform clinical decision-making and to plan specific rehabilitation interventions by physiotherapists for stroke survivors with upper limb spasticity.
Systematic Review Registration Number PROSPERO (ID: CRD42016027642).     

Attitudes of people with osteoarthritis towards their conservative management: a systematic review and meta-ethnography

This paper determines the perceptions of people diagnosed with osteoarthritis towards their conservative management strategies. A systematic review of the published (AMED, CINAHL, EMBASE, PsychINFO, SportsDisc, MEDLINE, Cochrane Clinical Trials Registry, PubMed) and unpublished/trial registry databases (WHO International Clinical Trials Registry Platform, Current Controlled Trials, the United States National Institute of Health Trials Registry, NIHR Clinical Research Portfolio Database) searched from their inception to July 2013. Eligible studies included those which presented the attitudes or perceptions of people with osteoarthritis towards non-operative management strategies. Study quality was appraised using the CASP and the Gough’s weight of evidence appraisal tools. Data were analysed through a meta-ethnography approach. Thirty-three studies including 1,314 people with osteoarthritis were sampled; the majority diagnosed with knee osteoarthritis. The overarching themes indicated people with osteoarthritis delay their diagnosis, opting for self-management and informal information gathering. This informal rather than health professional-led guidance is sought and maintained as an important resource throughout the care of this population and is valued. Diagnosis is sought at a ‘critical point’. Healthcare interventions largely provided are poorly perceived. The period of subsequent self-management is an expectation before the inevitable requirement for joint replacement. There remains uncertainty regarding when this is required, but the expected failure of conservative treatment to manage pain and symptoms is common. In conclusion, patients should be enthused towards the principles of self-management and clinicians should not trivialise osteoarthritis. This may provide a more valuable perception of non-operative management to promote its adoption and adherence in managing osteoarthritis.     

The efficacy and safety of venetoclax therapy in elderly patients with relapsed,refractory chronic lymphocytic leukaemia

Elderly chronic lymphocytic leukaemia (CLL) patients treated outside of trials have notably greater toxicity with the Bruton's tyrosine kinase inhibitor ibrutinib compared to younger patients. It is not known whether the same holds true for the B-cell lymphoma 2 inhibitor venetoclax. We provide a comprehensive analysis of key safety measures and efficacy in 342 patients comparing age categories ≥75 and <75 years treated in the relapsed, refractory non-trial setting. We demonstrate that venetoclax has equivalent efficacy and safety in relapsed/refractory CLL patients who are elderly, the majority of whom are previous ibrutinib-exposed and therefore may otherwise have few clear therapeutic options.