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.
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.
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.