Dual muscarinic antagonists and β2-agonists (MABAs) represent a promising therapeutic class for the treatment of asthma and chronic obstructive pulmonary disease (COPD). We report the discovery and optimization of MABAs by integrating a diarylsulfone scaffold with the hydroxyquinoline moiety of indacaterol 2 to achieve dual M3 and β2 activity. Through SAR studies to optimize the linker design and M3-targeting features, a novel MABA series was realized with excellent affinity at M3/β2 receptors. Lead compounds 150 and 160 showed high-affinity and long-lived binding to M3 (Ki: 1.95 nM and 1.75 nM, respectively, at 24 h) and subnanomolar β2-agonist potency, along with excellent (EC50 < 10 nM) smooth muscle relaxant activity in carbachol-stimulated guinea pig trachea rings. Moreover, after intratracheal administration, both compounds exhibited sustained in vivo bronchoprotection for 24 h in the modified Einthoven model of acute bronchoconstriction, with equivalent efficacy to the clinical-stage MABA batefenterol 9. Further development of these compounds is warranted as inhaled bronchodilators.

Pulmonary fibrosis (PF) can lead to respiratory distress, persistent dry cough, and a decline in quality of life, and may be life-threatening in severe cases. The aim is to mine and analyze drug-related PF signals, summarize potential risk medications, and provide references for clinical medication safety. This research accessed data from the US Food and Drug Administration Adverse Event Reporting System covering reports from January 2004 to September 2024. Proportional disproportionality methods were utilized to explore the relationship between drugs and PF, and to assess demographic information, drug-related PF risks, and the timing of PF onset. The Food and Drug Administration Adverse Event Reporting System database contained reports of 830 drugs associated with PF. Through disproportionality analysis and subsequent filtering, 33 drugs were identified as having significant risks. Fifteen antitumor and immunomodulatory drugs (45.45%) were noted, including bleomycin (reporting odds ratio [ROR] = 41.68), interferon gamma-1B (ROR = 12.11), and anagrelide (ROR = 6.63). Four cardiovascular system drugs (12.12%) included amiodarone (ROR = 41.92), dronedarone (ROR = 10.25), and simvastatin (ROR = 6.94). Four respiratory system drugs (12.12%) included indacaterol (ROR = 6.87), salmeterol/fluticasone (ROR = 4.30), and olodaterol (ROR = 3.76). Four antipathogenic microbial drugs (12.12%) included nitrofurantoin (ROR = 22.92), sulfasalazine (ROR = 5.69), and hydroxychloroquine (ROR = 3.51). Six other drugs (18.18%) included iodine-131 (ROR = 19.72), calcium carbonate (ROR = 8.59), and tamsulosin (ROR = 7.48). Amiodarone (Bayesian confidence propagation neural network [BCPNN] = 5.26), bleomycin (BCPNN = 4.95), and nitrofurantoin (BCPNN = 4.40) were the 3 drugs characterized by the greatest associated PF risk. The time to PF onset from antitumor and immunomodulatory drugs was significantly shorter than that from other drug types (P = .0082). The study identified 33 drugs showing disproportionality signals suggestive of potential associations with PF, most notably among antitumor and immunomodulatory agents, which exhibited a significantly shorter time to PF onset compared with other drug classes. The 3 drugs associated with the greatest PF risk were amiodarone, bleomycin, and nitrofurantoin. These findings highlight potential pharmacovigilance signals that warrant clinical vigilance and further validation through prospective studies.

Metastasis remains the leading cause of cancer-related mortality, driven by multifaceted interactions within the tumor microenvironment (TME). Recently, Neutrophil Extracellular Traps (NETs) have emerged as critical facilitators of metastatic progression. This study aimed to systematically screen FDA-approved drugs to identify novel NET inhibitors and evaluate the potential of indacaterol (IND) as an anti-metastatic agent. The screening identified IND as a potent inhibitor of NETosis (IC50 = 6.567 μM), significantly suppressing extracellular DNA release and Citrullinated Histone H3 expression in a dose-dependent manner. In vitro investigations revealed that IND exerts a dual therapeutic effect: directly inhibiting tumor cell proliferation and migration, and indirectly restoring anti-tumor immunity by dismantling the NET barrier, evidenced by revitalized CD8 + T cell activation (CD25 +) and IFN-γ secretion. Additionally, IND promoted macrophage polarization toward an M2 phenotype, facilitating the phagocytic clearance of NETs. In vivo, IND treatment markedly reduced circulating NET levels and significantly suppressed metastatic colonization in the liver and spleen. This study provides the first systematic evidence positioning Indacaterol as a novel and potent NETs inhibitor. By effectively blocking NET formation and remodeling the immune microenvironment, IND demonstrates significant anti-metastatic potential. Leveraging its established pharmacological and safety profile, Indacaterol represents a promising candidate for rapid clinical repurposing to target NET-mediated metastasis, particularly in malignancies characterized by systemic inflammation.

Dry powder inhalers (DPIs) are rarely used during invasive mechanical ventilation (IMV) because intubated patients cannot generate sufficient inspiratory effort, and ventilator circuits require heated humidification that may impair powder dispersion. This study evaluated whether a ventilator-actuated, enclosed DPI chamber combined with a rapidly adjustable absolute humidifier can enable efficient DPI delivery under clinically relevant IMV conditions. An in vitro IMV model was operated in volume-controlled ventilation (15 breaths/min; I:E 1:2; square waveform; peak flow 50 L/min). An enclosed delivery chamber housing a capsule DPI (Breezhaler®; indacaterol 150 µg with lactose carriers) was inserted in-line during expiration and actuated for 15 breaths. Circuit humidity was controlled using an Absolute Humidifier Prototype at 0, 11, 22, 33, and 44 mg/L absolute humidity (AH; 0-100% RH at 37 °C) and compared with a pass-over humidifier (MR850; ∼40 mg/L AH). Tidal volume (VT) was 400-800 mL, and endotracheal tube (ETT) size was 7.5 or 9.5 mm internal diameter (ID). Inhaled dose was defined as the drug mass collected on the inspiratory filter distal to the ETT, and the aerodynamic particle size distribution (APSD) of inhaled dose was measured using an NGI. Inhaled dose showed a bidirectional dependence on humidity. At VT 600 mL with a 7.5-mm ETT, the inhaled dose peaked at 39.9 ± 0.9% of the labeled dose at 22 mg/L AH, decreased slightly at 33 mg/L AH (32.0 ± 1.6%), and dropped markedly near saturation at 44 mg/L AH (10.0 ± 2.2%); MR850 produced a similarly low inhaled dose (10.8 ± 1.2%). Increasing ETT ID from 7.5 to 9.5 mm reduced ETT deposition across 0-33 mg/L AH (e.g., 10.3 ± 0.7% to 5.8 ± 0.7% at 0 mg/L, p < 0.05) and increased inhaled dose at low humidity (e.g., 28.4 ± 2.0% to 36.3 ± 2.5% at 0 mg/L, p < 0.05). VT had little influence at 0-22 mg/L AH, but at high humidity, the inhaled dose increased (44 mg/L AH, 9.5-mm ETT: 13.3 ± 1.9 µg at VT 400 vs 37.0 ± 4.2 µg at VT 800, p < 0.05). APSD was largely stable across humidity and VT. Mass median aerodynamic diameter remained 2.76 ± 0.15 to 3.07 ± 0.03 µm, and geometric standard deviation showed no significant humidity effect. Fine particle dose (<5 µm) peaked at 26.1 ± 4.6 µg at 11 mg/L AH and decreased to 8.0 ± 2.7 µg at 44 mg/L AH (p < 0.05). A ventilator-actuated, enclosed chamber, combined with real-time humidity control, enabled efficient DPI delivery during IMV. Delivery was optimized at intermediate humidity (22 mg/L AH) and reduced at both humidity extremes. These data indicated controllable humidification is critical for translating DPI therapy into mechanically ventilated care.

This study describes the development and validation of stability-indicating analytical methods for indacaterol maleate, an ultra-long-acting β2-adrenoceptor agonist used in asthma and chronic obstructive pulmonary disease (COPD). RP-HPLC-UV methods were established for quantifying indacaterol and its related substances, while LC-QDa-MS and high-resolution LC-QTOF-MS were employed for impurity identification and structural elucidation. All methods were developed and validated in accordance with ICH guidelines to support comprehensive assessment of process-related impurities and degradation behavior. Eight potential impurities were identified, synthesized, and fully characterized. The validated RP-HPLC-UV assay and related substances methods were applied to forced degradation studies under thermal, photolytic, oxidative, neutral, acidic, and alkaline conditions, as well as to accelerated and long-term stability samples. Trace-level impurities were structurally elucidated using LC-QDa-MS and LC-QTOF-MS. In silico mutagenicity assessment of thirteen impurities using Nexus software classified IND-B ((R)-8-(benzyloxy)-5-(2-bromo-1-hydroxyethyl)-quinolin-2(1H)-one) as a Class 3 potential genotoxic impurity due to its alkyl bromide moiety. Although the TTC-based limit for IND-B (based on the ICH M7 threshold of 1.5 µg/day for a maximum daily dose of 300 µg) corresponds to ≤ 0.5%, all specified impurities were conservatively controlled at ≤ 0.15% and unspecified impurities at ≤ 0.10%, in line with ICH M7 and Q3A guidelines. The RP-HPLC-UV assay and related substances methods demonstrated specificity, precision, accuracy, linearity, and robustness, confirming their suitability as stability-indicating methods. Overall, this integrated approach provides a robust framework for impurity profiling, stability assessment, and genotoxic risk evaluation of indacaterol maleate, ensuring regulatory compliance and product quality throughout shelf life.

Liposomes are promising carriers for pulmonary drug delivery due to their biocompatibility and controlled-release properties. However, their stability in aqueous suspension is limited, leading to aggregation and reduced therapeutic efficiency. Converting liposomal dispersions into dry powders for inhalation (DPIs) is a potential strategy to overcome these limitations. Spray-drying (SD) is particularly attractive for this purpose, offering precise control over particle properties along with speed, cost-efficiency, and scalability. Yet, the thermal and mechanical stresses involved in this process and their effects on liposomal integrity remain poorly understood, limiting its broader application. In this study, we developed a systematic framework integrating Design of Experiments (DOE) with scale-up-oriented processing, combining supercritical fluid technology (PGSS) for liposome formation with subsequent spray-drying of high solid content suspensions. Two complementary DoE approaches were applied: DOEA optimized drying parameters and carbohydrate type, testing trehalose and hydroxypropyl-β-cyclodextrin (HPβCD), while DOEB assessed the effects of active pharmaceutical ingredients (APIs) hydrophobicity, lipid composition (1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000 (DSPE-PEG2000) percentage), and carbohydrate-to-liposome ratio. Optimized spray-dried powders exhibited preserved liposome structure (mean diameter < 200 nm, narrow polydispersity index (PdI), near-neutral zeta potential (ZP)), favorable aerodynamic properties (∼3 µm, extra-fine particle fraction (eFPF) > 20% and fine particle fraction (FPF) > 60%), low residual moisture (<5%), and high drying yields (>75%). Mechanistic insights revealed that HPβCD significantly protects liposomes during atomization, while drug retention was governed by PEGylated lipid content, lipid-to-carbohydrate ratio, and API hydrophobicity. Co-encapsulation of clinically relevant drug combinations (formoterol/budesonide and ciclesonide/indacaterol) produced uniform powders with efficient aerosolization, highlighting the therapeutic potential of these formulations. Collectively, these results establish a robust, scalable, and reproducible approach for designing liposomal DPIs, balancing formulation composition, excipient selection, and process parameters. This study demonstrates that strategic integration of scalable technologies can reconcile structural stability, aerodynamic performance, and manufacturability, paving the way for the industrial translation of liposomal dry powders for targeted pulmonary therapies, including asthma and chronic obstructive pulmonary disease (COPD).

Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disorder caused by loss-of-function variants in the sphingomyelin phosphodiesterase-1 (SMPD1) gene encoding for the acid sphingomyelinase (ASM). Aberrantly high levels of sphingosylphosphorylcholine (SPC), the deacylated form of sphingomyelin which is the primary accumulated lipid, are key biomarkers in ASMD. The identification of small molecules targeting SPC is an attractive approach for treating ASMD. We screened 1813 Food and Drug Administration-approved compounds to identify promising candidates that reduce SPC for treating ASMD, using a liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) assay. Eight compounds, floxuridine, dexamethasone, indacaterol maleate, triethylenethiophosphoramide, cytarabine, doramectin, cepharanthine (CEP), and tetrandrine (TE), were identified to abate the accumulation of SPC in ASMD cells. CEP and TE were selected for further pharmacological studies because of their ability to confer the greatest reduction effect on SPC. Finally, a reduction of SPC storage was verified in ASMD lymphoblasts, SMPD1-KO cells and SMPD1[Y496H] fibroblasts by CEP treatment. Additionally, CEP could improve mitochondrial morphology and function, and stimulated lysosome biogenesis by promoting TFEB nuclear translocation in ASMD cells. These results suggest that CEP could potentially be developed as a promising candidate for treating ASMD.

Chronic Obstructive Pulmonary Disease (COPD) is a respiratory condition defined by persistent bronchitis, emphysema, and structural remodelling. The number of cases has risen globally; however, limited viable remedies exist. It is linked to airway blockage, oxidative stress, chronic conditions, inflammation, excessive mucus production, and increased autophagy and cellular senescence. Beta-2 adrenergic receptors (β2-ARs) play a significant role in both the aetiology and management of COPD. Beta-2 agonists (particularly long-acting beta-agonists, or LABAs) are preferable in COPD therapy due to their powerful bronchodilation, rapid onset, prolonged duration, and potential synergistic effects with other medications. They are well-tolerated and effective in improving the quality of life and reducing exacerbations, making them an essential component of COPD treatment. Currently, there are fewer bronchodilators that have been found to be effective. This leads to an exploration of novel, long-acting, and ultra-long-acting drugs for the management of COPD. This article provides an extensive overview of natural β2 agonists. The current study emphasizes the rational development of lead candidates, including trantinterol, isopropyl, tert-butyl, and heterocyclic ring 2-amino-2-phenylethanol derivatives, 8-(2-amino-1-hydroxyethyl)-6-hydroxy-1,4- benzoxazine-3(4H)-one derivatives (non-substituted, methyl-substituted, dimethyl-substituted), 5- (2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one analogues, indacaterol analogues, saligenin antedrugs, and saligenin alkoxyalkylphenyl sulfonamide derivatives, accompanied by molecular docking studies. This paper also highlights numerous structure-activity relationship investigations and various novel β2 agonists currently in clinical trials and patents. The present review will significantly aid in fostering the research of COPD.