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Pulmonary arterial hypertension is a progressive disease involving proliferative remodeling of the pulmonary vessels. Despite therapeutic advances, the disease-associated morbidity and mortality remain high. Sotatercept is a fusion protein that traps activins and growth differentiation factors involved in pulmonary arterial hypertension. We conducted a multicenter, double-blind, phase 3 trial in which adults with pulmonary arterial hypertension (World Health Organization [WHO] functional class II or III) who were receiving stable background therapy were randomly assigned in a 1:1 ratio to receive subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; target dose, 0.7 mg per kilogram) or placebo every 3 weeks. The primary end point was the change from baseline at week 24 in the 6-minute walk distance. Nine secondary end points, tested hierarchically in the following order, were multicomponent improvement, change in pulmonary vascular resistance, change in N-terminal pro-B-type natriuretic peptide level, improvement in WHO functional class, time to death or clinical worsening, French risk score, and changes in the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) Physical Impacts, Cardiopulmonary Symptoms, and Cognitive/Emotional Impacts domain scores; all were assessed at week 24 except time to death or clinical worsening, which was assessed when the last patient completed the week 24 visit. A total of 163 patients were assigned to receive sotatercept and 160 to receive placebo. The median change from baseline at week 24 in the 6-minute walk distance was 34.4 m (95% confidence interval [CI], 33.0 to 35.5) in the sotatercept group and 1.0 m (95% CI, -0.3 to 3.5) in the placebo group. The Hodges-Lehmann estimate of the difference between the sotatercept and placebo groups in the change from baseline at week 24 in the 6-minute walk distance was 40.8 m (95% CI, 27.5 to 54.1; P<0.001). The first eight secondary end points were significantly improved with sotatercept as compared with placebo, whereas the PAH-SYMPACT Cognitive/Emotional Impacts domain score was not. Adverse events that occurred more frequently with sotatercept than with placebo included epistaxis, dizziness, telangiectasia, increased hemoglobin levels, thrombocytopenia, and increased blood pressure. In patients with pulmonary arterial hypertension who were receiving stable background therapy, sotatercept resulted in a greater improvement in exercise capacity (as assessed by the 6-minute walk test) than placebo. (Funded by Acceleron Pharma, a subsidiary of MSD; STELLAR ClinicalTrials.gov number, NCT04576988.).

The inhalation route is frequently used to administer drugs for the management of respiratory diseases such as asthma or chronic obstructive pulmonary disease. Compared with other routes of administration, inhalation offers a number of advantages in the treatment of these diseases. For example, via inhalation, a drug is directly delivered to the target organ, conferring high pulmonary drug concentrations and low systemic drug concentrations. Therefore, drug inhalation is typically associated with high pulmonary efficacy and minimal systemic side effects. The lung, as a target, represents an organ with a complex structure and multiple pulmonary-specific pharmacokinetic processes, including (1) drug particle/droplet deposition; (2) pulmonary drug dissolution; (3) mucociliary and macrophage clearance; (4) absorption to lung tissue; (5) pulmonary tissue retention and tissue metabolism; and (6) absorptive drug clearance to the systemic perfusion. In this review, we describe these pharmacokinetic processes and explain how they may be influenced by drug-, formulation- and device-, and patient-related factors. Furthermore, we highlight the complex interplay between these processes and describe, using the examples of inhaled albuterol, fluticasone propionate, budesonide, and olodaterol, how various sequential or parallel pulmonary processes should be considered in order to comprehend the pulmonary fate of inhaled drugs.

Abstract Rationale The most effective approach to teaching respiratory inhaler technique is unknown. Objectives To evaluate the relative effects of two different educational strategies (teach-to-goal instruction vs. brief verbal instruction) in adults hospitalized with asthma or chronic obstructive pulmonary disease. Methods We conducted a randomized clinical trial at two urban academic hospitals. Participants received teach-to-goal or brief instruction in the hospital and were followed for 90 days after discharge. Inhaler technique was assessed using standardized checklists; misuse was defined as 75% steps or less correct (≤9 of 12 steps). The primary outcome was metered-dose inhaler misuse 30 days postdischarge. Secondary outcomes included Diskus technique; acute care events at 30 and 90 days; and associations with adherence, health literacy, site, and patient risk (near-fatal event). Measurements and Main Results: Of 120 participants, 73% were female and 90% were African American. Before education, metered-dose inhaler misuse was similarly common in the teach-to-goal and brief intervention groups (92% vs. 84%, respectively; P = 0.2). Metered-dose inhaler misuse was not significantly less common in the teach-to-goal group than in the brief instruction group at 30 days (54% vs. 70%, respectively; P = 0.11), but it was immediately after education (11% vs. 60%, respectively; P < 0.001) and at 90 days (48% vs. 76%, respectively; P = 0.003). Similar results were found with the Diskus device. Participants did not differ across education groups with regard to rescue metered-dose inhaler use or Diskus device adherence at 30 or 90 days. Acute care events were less common among teach-to-goal participants than brief intervention participants at 30 days (17% vs. 36%, respectively; P = 0.02), but not at 90 days (34% vs. 38%, respectively; P = 0.6). Participants with low health literacy receiving teach-to-goal instruction were less likely than brief instruction participants to report acute care events within 30 days (15% vs. 70%, respectively; P = 0.008). No differences existed by site or patient risk at 30 or 90 days (P > 0.05). Conclusions In adults hospitalized with asthma or chronic obstructive pulmonary disease, in-hospital teach-to-goal instruction in inhaler technique did not reduce inhaler misuse at 30 days, but it was associated with fewer acute care events within 30 days after discharge. Inpatient treatment-to-goal education may be an important first step toward improving self-management and health outcomes for hospitalized patients with asthma or chronic obstructive pulmonary disease, especially among patients with lower levels of health literacy. Clinical trial registered with www.clinicaltrials.gov (NCT01426581).

The lung surfactant (LS) lining is a thin liquid film covering the air–liquid interface of the respiratory tract. LS reduces surface tension, enabling lung surface expansion and contraction with minimal work during respiration. Disruption of surface tension is believed to play a key role in severe lung conditions. Inhalation of aerosols that interfere with the LS may induce a toxic response and, as a part of the safety assessment of chemicals and inhaled medicines, it may be relevant to study their impact on LS function. Here, we present a novel in vitro method, based on the constrained drop surfactometer, to study LS functionality after aerosol exposure. The applicability of the method was investigated using three inhaled asthma medicines, micronized lactose, a pharmaceutical excipient used in inhaled medication, and micronized albumin, a known inhibitor of surfactant function. The surfactometer was modified to allow particles mixed in air to flow through the chamber holding the surfactant drop. The deposited dose was measured with a custom-built quartz crystal microbalance. The alterations allowed the study of continuously increasing quantified doses of particles, allowing determination of the dose of particles that affects the LS function. The tested pharmaceuticals did not inhibit the function of a model LS even at extreme doses—neither did lactose. Micronized albumin, however, impaired surfactant function. The method can discriminate between safe inhaled aerosols—as exemplified by the approved inhaled medicines and the pharmaceutical excipient lactose—and albumin known to impair lung functionality by inhibiting LS function.

Abstract Background: Loxapine, a first-generation antipsychotic, delivered with a novel inhalation delivery device developed for the acute treatment of agitation in patients with schizophrenia or bipolar disorder was evaluated in subjects with asthma or chronic obstructive pulmonary disease (COPD). Methods: Separate randomized, double-blind, parallel-arm, placebo-controlled trials compared two administrations of inhaled loxapine (10 mg) 10 hr apart with placebo in 52 subjects with asthma and in 53 subjects with COPD. A thermally-generated drug aerosol of loxapine was delivered to the deep lung for rapid systemic absorption. Controller medications were continued throughout the study, but quick-relief bronchodilators were withheld from 6–8 hr before through 34 hr after dose 1, unless indicated as rescue. Results: All airway adverse events (AEs) were of mild or moderate severity. Symptomatic bronchospasm occurred in 53.8% of subjects with asthma after inhaled loxapine and 11.5% after placebo; and in 19.2% of COPD subjects after inhaled loxapine and 11.1% after placebo. Subjects required inhaled albuterol as follows: asthma: 53.8% after inhaled loxapine and 11.5% after placebo; and COPD: 23.1% after inhaled loxapine and 14.8% after placebo. Respiratory signs/symptoms requiring treatment responded to rescue bronchodilator [forced expiratory volume in 1 sec (FEV1) return to within 10% of baseline] within 1 hr in 11 of 15 events in asthma subjects and four of seven events in COPD subjects, the remainder by the last spirometry. Conclusions: In subjects with either asthma or COPD, FEV1 decline and bronchospasm can occur following inhaled loxapine, but more frequently in asthmatic subjects. Most subjects with bronchospasm responded to rescue bronchodilator within 1 hr. No treatment-related serious AE occurred. Although inhaled loxapine is contraindicated in patients with active airways disease per the current approved US labeling, these studies demonstrated that rescue bronchodilator mitigated the symptomatic bronchospasms that may occur in case of inadvertent use.

Valved holding chambers (VHCs) have been used with pressurized metered-dose inhalers since the early 1980s. They have been shown to increase fine particle delivery to the lungs, decrease oropharyngeal deposition, and reduce side effects such as throat irritation, dysphonia, and oral candidiasis that are common with use of pressurized metered-dose inhalers (pMDIs) alone. VHCs act as aerosol reservoirs, allowing the user to actuate the pMDI device and then inhale the medication in a two-step process that helps users overcome challenges in coordinating pMDI actuation with inhalation. The design of VHC devices can have an impact on performance. Features such as antistatic properties, effective face-to-facemask seal feedback whistles indicating correct inhalation speed, and inhalation indicators all help improve function and performance, and have been demonstrated to improve asthma control, reduce the rate of exacerbations, and improve quality of life. Not all VHCs are the same, and they are not interchangeable. Each pairing of a pMDI device plus VHC should be considered as a unique delivery system.

Recurrence of acute exacerbations has a major impact on patients with COPD. Therefore, effective prevention and treatment of exacerbation is crucial in the management of COPD, especially for patients with moderate to severe disease. This study evaluated the effectiveness of YuPingFeng granule administration in preventing exacerbation and improving symptom score, as well as its long-term (1 year) safety profile, in patients with COPD. This was a randomized, double-blind, parallel, placebo-controlled study of 240 patients from eight centers in China. Participants were eligible if they had mild to severe COPD as defined by Global Initiative for Chronic Obstructive Lung Disease, had a history of at least two COPD exacerbations or one hospitalization within the previous year, and had remained clinically stable for over 4 weeks before the study. They were randomly assigned to receive 5 g of YuPingFeng or placebo, three times per day, for 1 year. The primary end point was the exacerbation rate over 1 year, and the analysis was by intention to treat. Secondary end points included symptom score, which was assessed by COPD assessment test (CAT) score and safety profiles. This trial was registered in the Chinese Clinical Trial Registry (http://www.chictr.org.cn; registration number: ChiCTR-IPR-15007023). The YuPingFeng group had a significantly lower exacerbation rate than the placebo group (1.15 vs 1.55; risk ratio=0.677 [95% CI 0.531-0.863]; =0.002) and a significantly reduced risk of second exacerbation (95% CI 0.326-0.772; =0.002). After treatment, the mean change in the CAT score in the YuPingFeng group (-4.41±7.01) differed significantly from that in the placebo group (-2.49±5.31; =0.001). YuPingFeng was well tolerated. YuPingFeng granules can be considered as a treatment option for COPD; this treatment prevents acute exacerbations of COPD and has a good safety profile.

To assess the comparative efficacy of short-acting muscarinic antagonists (SAMAs), long-acting muscarinic antagonists (LAMAs), LAMA in combination with long-acting beta-agonists (LABAs; LAMA/LABAs) and inhaled corticosteroids (ICS) in combination with LABA (ICS/LABAs) for the maintenance treatment of COPD. We systematically reviewed 74 randomized controlled trials (74,832 participants) published up to 15 November 2017, which compared any of the interventions (SAMA [ipratropium], LAMA [aclidinium, glycopyrronium, tiotropium, umeclidinium], LAMA/LABA [aclidinium/formoterol, indacaterol/glycopyrronium, tiotropium/olodaterol, umeclidinium/vilanterol] and ICS/LABA [fluticasone/vilanterol, budesonide/formoterol, salmeterol/fluticasone]) with each other or with placebo. A random-effects network meta-analysis combining direct and indirect evidence was conducted to examine the change from baseline in trough FEV , transition dyspnea index, St George's Respiratory Questionnaire and frequency of adverse events at weeks 12 and 24. Inconsistency models were not statistically significant for all outcomes. LAMAs, LAMA/LABAs and ICS/LABAs led to a significantly greater improvement in trough FEV compared with placebo and SAMA monotherapy at weeks 12 and 24. All LAMA/LABAs, except aclidinium/formoterol, were statistically significantly better than LAMA monotherapy and ICS/LABAs in improving trough FEV . Among the LAMAs, umeclidinium showed statistically significant improvement in trough FEV at week 12 compared to tiotropium and glycopyrronium, but the results were not clinically significant. LAMA/LABAs had the highest probabilities of being ranked the best agents in FEV improvement. Similar trends were observed for the transition dyspnea index and St George's Respiratory Questionnaire outcomes. There were no significant differences in the incidences of adverse events among all treatment options. LAMA/LABA showed the greatest improvement in trough FEV at weeks 12 and 24 compared with the other inhaled drug classes, while SAMA showed the least improvement. There were no significant differences among the LAMAs and LAMA/LABAs within their respective classes.

Acute respiratory distress syndrome (ARDS) is a syndrome of acute lung injury that is characterized by noncardiogenic pulmonary edema and severe hypoxemia second to a pathogenic impairment of gas exchange. Despite significant advances in the area, mortality remains high among ARDS patients. High mortality and a limited spectrum of therapeutic options have left clinicians searching for alternatives, spiking interest in selective pulmonary vasodilators (SPVs). Despite the lack of robust evidence, SPVs are commonly employed for their therapeutic role in improving oxygenation in patients who have developed refractory hypoxemia in ARDS. While inhaled epoprostenol (iEPO) also impacts arterial oxygenation by decreasing ventilation–perfusion (V/Q) mismatching and pulmonary shunt flow, this effect is not different from inhaled nitric oxide (iNO). The most effective and safest dose for yielding a clinically significant increase in PaO2 and reduction in pulmonary artery pressure (PAP) appears to be 20–30 ng/kg/min in adults and 30 ng/kg/min in pediatric patients. iEPO appears to have a ceiling effect above these doses in which no additional benefit may be derived. iNO and iEPO have shown similar efficacy profiles; however, they differ with respect to cost and ease of therapeutic administration. The most beneficial effects of iEPO have been seen in adult patients with secondary ARDS as compared with primary ARDS, most likely due to the difference in etiology of the two disease states, and in patients suffering from baseline right ventricular heart failure. Although iEPO has demonstrated improvements in hemodynamic parameters and oxygenation in ARDS patients, due to the limited number of randomized clinical trials and the lack of studies investigating mortality, the use of iEPO cannot be recommended as standard of care in ARDS. iEPO should be reserved for those refractory to traditional therapies.