Daily Respiratory Research Analysis
A multicenter phase 2 RCT showed that once-daily sultiame produced dose-dependent improvements in obstructive sleep apnea severity and symptoms. A PNAS preclinical study introduced a membrane-stabilizing bottlebrush copolymer that prevented skeletal/diaphragm damage and stress-induced cardiac death in DMD models. A population-based cohort across Finland and Scotland linked antenatal corticosteroids to higher long-term respiratory and nonrespiratory infection risks in children born ≥34 weeks.
Summary
A multicenter phase 2 RCT showed that once-daily sultiame produced dose-dependent improvements in obstructive sleep apnea severity and symptoms. A PNAS preclinical study introduced a membrane-stabilizing bottlebrush copolymer that prevented skeletal/diaphragm damage and stress-induced cardiac death in DMD models. A population-based cohort across Finland and Scotland linked antenatal corticosteroids to higher long-term respiratory and nonrespiratory infection risks in children born ≥34 weeks.
Research Themes
- Pharmacologic therapy for obstructive sleep apnea
- Membrane-stabilizing biomaterials for respiratory muscle protection
- Perinatal interventions and long-term infection risk
Selected Articles
1. Sultiame once per day in obstructive sleep apnoea (FLOW): a multicentre, randomised, double-blind, placebo-controlled, dose-finding, phase 2 trial.
Once-daily sultiame reduced AHI3a in a dose-dependent fashion at 15 weeks and improved sleep-related outcomes, with paraesthesia and headache being the most common adverse events. Benefits were observed across multiple nocturnal and daytime measures, supporting carbonic anhydrase inhibition as a pharmacologic strategy in OSA.
Impact: This is a rare, well-powered, double-blind RCT demonstrating pharmacologic efficacy in OSA, a field dominated by device therapy. It opens a therapeutic pathway with measurable physiologic and patient-reported benefits.
Clinical Implications: Sultiame may offer an adjunct or alternative for OSA patients who are intolerant of CPAP or seeking pharmacologic options. Clinicians should monitor dose-related paresthesia and consider patient selection while awaiting phase 3 outcomes.
Key Findings
- Placebo-subtracted relative AHI3a change at 15 weeks: -16.4% (100 mg), -30.2% (200 mg), -34.6% (300 mg).
- Improvements extended to nocturnal hypoxia, sleep quality, and daytime sleepiness measures.
- Adverse events were dose-dependent; paresthesia occurred in 22% (100 mg), 43% (200 mg), and 57% (300 mg).
Methodological Strengths
- Multicenter, randomized, double-blind, placebo-controlled dose-finding design.
- Pre-specified estimands framework with stratification by baseline AHI.
Limitations
- Phase 2 duration (15 weeks) without long-term outcomes or head-to-head comparison with standard care (e.g., CPAP).
- Dose-related adverse events may limit tolerability at higher doses.
Future Directions: Confirm efficacy and safety in phase 3 trials, define optimal dosing and patient phenotypes responsive to carbonic anhydrase inhibition, and evaluate combination with CPAP or oral appliances.
BACKGROUND: Obstructive sleep apnoea (OSA) is highly prevalent but approved pharmacological treatment options are missing. Sultiame improves the ventilatory response and upper airway muscle activity by inhibiting carbonic anhydrase. This study aimed to prospectively assess the efficacy and safety of three dosages of sultiame in OSA. METHODS: This multicentre, randomised, parallel, double-blind, placebo-controlled, dose-finding, phase 2 trial was performed at 28 hospitals and community-based sites in five European countries. Adults (aged 18-75 years) with untreated, moderate to severe OSA and an Apnoea-Hypopnea Index (AHI) of ≥15 to ≤50 events per h were randomly assigned (1:1:1:1), using interactive response technology, to receive placebo or sultiame 100 mg, 200 mg, or 300 mg tablets of identical appearance once per day at bedtime for 15 weeks. Randomisation was stratified by baseline AHI3a. The primary outcome measure for efficacy was the relative change of AHI3a from baseline to week 15 (scheduled treatment end). All participants who were randomly assigned were included in the primary efficacy analysis using an estimands framework and in the safety analysis. This trial is registered with EudraCT (2021-002926-26) and ClinicalTrials.gov (NCT05236842) and is complete. FINDINGS: Between Dec 2, 2021, and April 8, 2023, 535 patients were screened and 298 were randomly assigned to placebo (n=75), or sultiame 100 mg (n=74), 200 mg (n=74), or 300 mg (n=75). 240 patients completed 15 weeks of treatment. 220 (74%) of 298 participants were male and 78 (26%) were female. In the full analysis set, placebo-subtracted relative AHI3a adjusted means change at week 15 was -16·4% (95% CI -31·3 to -1·4; p=0·032), -30·2% (-45·4 to -15·1; p<0·0001), and 34·6% (-49·1 to -20·0; p<0·0001) for sultiame 100 mg, 200 mg, and 300 mg, respectively. The incidence of adverse events increased dose-dependently: 46 (61%) of 75 patients in the placebo group, 54 (73%) of 74 in the 100 mg group, 62 (84%) of 74 in the 200 mg group, and 68 (91%) of 75 in the 300 mg group.
2. Synthetic bottlebrush block copolymer prevents disease onset in Duchenne muscular dystrophy.
A bottlebrush block copolymer targeting membrane stability restored contractility in DMD muscle fibers in vitro and prevented skeletal/diaphragm damage and stress-induced cardiac injury and death in vivo. Its potency (~150,000× vs linear polymers) positions it as a stand-alone membrane-stabilizing therapeutic candidate.
Impact: Introduces a mechanistically novel, highly potent macromolecular therapy that protects respiratory and cardiac muscles in DMD models, addressing a central disease mechanism (membrane instability).
Clinical Implications: While preclinical, the approach suggests an early-life prophylactic strategy to preserve diaphragm and cardiac function in DMD, potentially complementing gene or exon-skipping therapies. Translation will require toxicology, pharmacokinetics, and delivery optimization.
Key Findings
- Bottlebrush copolymer was ~150,000-fold more potent than linear polymers in restoring skeletal muscle fiber contractility in vitro.
- In DMD animals, it prevented skeletal and diaphragm muscle damage onset and blocked stress-induced cardiac injury and death.
- Targets membrane instability as a druggable central defect, suggesting stand-alone membrane-stabilizing therapy.
Methodological Strengths
- Mechanistically grounded design targeting membrane instability with in vitro and in vivo validation.
- Demonstrated efficacy in multiple organs (skeletal, diaphragm, heart) relevant to DMD morbidity.
Limitations
- Preclinical animal data without human safety/efficacy.
- Details on dosing, biodistribution, long-term toxicity, and manufacturability remain to be established.
Future Directions: Advance to GLP toxicology, pharmacokinetics, and delivery studies; evaluate combination with gene therapies; assess chronic dosing, immunogenicity, and functional outcomes (respiratory, cardiac) in larger animal models.
Duchenne muscular dystrophy (DMD) is a fatal genetic disease of progressive muscle deterioration with no cure. DMD treatment requires a body-wide approach to target all diseased striated muscles: limb, respiratory, and heart. To address this, we focus studies on blocking the onset of muscle membrane instability, the primary defect in DMD, as a promising yet unmet druggable target. Here, data show the remarkable potency of a synthetic poly(ethylene oxide)/poly(propylene oxide) side chain-based bottlebrush block copolymer, ~150,000 times more potent than linear polymers, to rapidly restore contractile function to DMD skeletal muscle fibers in vitro. Strikingly, upon bottlebrush polymer delivery to DMD animals, results show highly efficacious prevention of the onset of skeletal and diaphragm muscle damage and the blocking of stress-induced cardiac injury and death in vivo. These data suggest bottlebrush polymers as a potent stand-alone muscle membrane-stabilizing therapeutic for DMD. Given DMD's early childhood onset, together with newborn screening for DMD, bottlebrush macromolecules could be envisioned as an early therapy to preserve and protect viable muscle and potentially for other acquired or inherited diseases involving membrane damage.
3. Antenatal Corticosteroids and Infectious Diseases Throughout Childhood.
In over 1.5 million mother–child pairs, antenatal corticosteroid exposure was associated with higher long-term risks of respiratory and nonrespiratory infections among late-preterm and term births, but not among births before 34 weeks. Findings argue for stricter ACS use and improved preterm birth prediction.
Impact: Shifts the risk-benefit discussion on ACS beyond neonatal outcomes to long-term infection susceptibility, with direct implications for obstetric decision-making.
Clinical Implications: For pregnancies ≥34 weeks at risk of delivery, clinicians should carefully weigh ACS benefits against potential long-term infection risks and prioritize accurate preterm birth prediction tools and stricter administration criteria.
Key Findings
- Among late-preterm (34–36+6 weeks) and term births, ACS exposure increased respiratory (HRs up to 1.27) and nonrespiratory infection risks (HRs up to 1.31).
- No association between ACS and infections was found in births before 34 weeks’ gestation.
- Incidence rates were higher in ACS-exposed vs unexposed: 65.2 vs 39.8 (respiratory) and 30.0 vs 17.9 (nonrespiratory) per 1000 person-years.
Methodological Strengths
- Very large, population-based cohort across two countries with registry linkage and gestational age stratification.
- Multivariable adjustment with hazard modeling and long-term follow-up up to 21 years.
Limitations
- Observational design with potential residual confounding and exposure misclassification.
- Lack of mechanistic biomarkers to explain increased infection susceptibility.
Future Directions: Refine ACS risk stratification (e.g., biomarker-informed prediction), assess dose–timing effects, and explore immune developmental mechanisms underlying long-term susceptibility.
IMPORTANCE: International guidelines recommend the use of antenatal corticosteroids (ACS) in pregnancies at risk of imminent preterm birth before 34 weeks' gestation. However, whether ACS leads to long-term risk of infection from childhood to adulthood is unknown. OBJECTIVE: To determine whether preterm (<37 weeks' gestation) and full-term (37-41 weeks' gestation) children exposed to ACS are more susceptible to respiratory and nonrespiratory infections compared with ACS-unexposed children throughout childhood and adolescence. DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study used data from the multicenter Consortium for the Study of Pregnancy Treatments (Co-OPT) study, including data from nationwide registries for mothers and their children in Finland and Scotland. Singleton children born from 1997 to 2018 and 2006 to 2018 in Scotland and Finland, respectively, were followed up until 2018, death, or first infection. Data were analyzed between June 2022 and October 2023. EXPOSURES: Maternal ACS treatment. MAIN OUTCOMES AND MEASURES: Primary and secondary outcomes were the first diagnosis of respiratory or nonrespiratory infection after birth-related hospital discharge. Outcomes were stratified by gestational age at birth. RESULTS: Among 1 548 538 included mother-child pairs (mean [SD] maternal age, 29.4 [5.7] years; mean [SD] gestational age at birth, 39.2 [1.7] weeks; 759 082 [49.0%] female neonates), 49 263 children (3.2%) were ACS-exposed, of whom 34 806 (70.7%) were preterm and 14 457 (29.3%) were full term at birth. ACS-exposed children had more respiratory and nonrespiratory infections than nonexposed children (incidence rate, 65.2 vs 39.8 and 30.0 vs 17.9 per 1000 person-years, respectively). Compared with nonexposed children, higher risks for respiratory and nonrespiratory infections were found among ACS-exposed children born at 34 weeks 0 days to 36 weeks 6 days' gestation (adjusted hazard ratios [HRs], 1.10 [95% CI, 1.06-1.14] and 1.19 [95% CI, 1.15-1.24]), 37 0/7 to 38 6/7 weeks' gestation (adjusted HRs, 1.27 [95% CI, 1.21-1.32] and 1.17 [95% CI, 1.11-1.23]), and 39 weeks 0 days to 41 weeks 6 days' gestation (adjusted HRs, 1.23 [95% CI, 1.16-1.30] and 1.31 [95% CI, 1.22-1.40]). However, ACS-exposed children born at 28 weeks 0 days to 31 weeks 6 days' gestation and 32 weeks 0 days to 33 weeks 6 days' gestation showed no association between ACS exposure and respiratory and nonrespiratory infections. CONCLUSION AND RELEVANCE: In this cohort study, exposure to ACS was associated with increased risks of infections in full-term children until age 21 years. In preterm children born before 34 weeks' gestation, no association between ACS and infections was found. To minimize the adverse effects of ACS treatment, more stringent criteria for ACS administration and better prediction tools for preterm birth are required.