Pulmonary pharmacology & therapeutics最新文献

Purpose

Oral treprostinil and selexipag are drugs targeting the prostacyclin pathway and are approved for treatment of pulmonary arterial hypertension (PAH). In the setting of unsatisfactory clinical response or tolerability issues while on selexipag, there is little data on clinical benefit, safety, or strategies on transitioning to oral treprostinil. Using prospective data from the ADAPT registry, we aimed to evaluate clinical outcomes, safety, and transition strategies in ten patients with PAH transitioning from selexipag to oral treprostinil.

Methods

ADAPT was a prospective, real-world, multicenter, United States-based registry of patients with PAH newly started on oral treprostinil, with a cohort of patients (n = 10) transitioning from selexipag to oral treprostinil. PAH variables of interest were collected from standard-of-care clinic visits. Clinical improvement was defined by modified REPLACE criterion, and risk was assessed by REVEAL Lite 2 from baseline to last follow-up. Real world transition strategies were recorded. Healthcare utilization or worsening PAH was evaluated within 30 days of transitions.

Results

Seven patients transitioned due to worsening PAH or lack of efficacy on selexipag, and three patients transitioned due to tolerability issues. Based on the modified REPLACE criterion, five patients demonstrated clinical improvement after transition from selexipag to oral treprostinil. Using REVEAL Lite 2 to assess risk, three patients improved and five patients maintained risk category from baseline to last follow-up. All transitions occurred in an outpatient setting either as abrupt stop/start or cross-titration, without parenteral treprostinil bridging.

Conclusion

Transition from selexipag to oral treprostinil was safe, performed without parenteral prostacyclin bridging, and resulted in clinical and categorical risk improvements in some patients.

Background

Recent advances in CFTR modulator therapy have the potential to change the face of cystic fibrosis (CF). This retrospective observational study describes real world experience of the four available CFTR modulators in adults and children with CF in a single centre in Melbourne, Australia.

Method

Data were collected for all patients treated with CFTR modulators at MonashCF between May 2012 and September 2020. Primary outcomes included lung function, admission days and BMI/BMI centile over time. Adverse events and reasons for changing or ceasing medications were also analysed.

Results

55% (74/133) adult and 46% (55/119) paediatric patients were treated with CFTR modulators. FEV1 increased in adults treated with ivacaftor (IVA) and elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) by 4.73% and 10.07% respectively, and BMI also improved in these groups. Nutrition improved in adults and children treated with lumacaftor/ivacaftor (LUM/IVA). There was no significant improvement in FEV1 or admission days with LUM/IVA or tezacaftor/ivacaftor (TEZ/IVA). 36% (31/85) ceased LUM/IVA, due to adverse effects in 81% (25/31). Of these, 92% (23/25) changed to TEZ/IVA, 78% (18/23) without significant adverse effects.

Conclusions

Our findings for LUM/IVA and TEZ/IVA are less encouraging than those seen in clinical trials, with no significant improvement in lung function or admission days and a higher rate of adverse effects with LUM/IVA compared with phase 3 clinical trials. TEZ/IVA was generally well tolerated by those who experienced side effects with LUM/IVA. The small number of patients treated with ELX/TEZ/IVA had improvements in all parameters. These findings support ongoing use of IVA for individuals with gating mutations, and transition to ELX/TEZ/IVA once available for patients with at least one Phe508del mutation.

Purpose

Chronic lung allograft dysfunction (CLAD) was a common complication following lung transplantation that contributed to long-term morbidity and mortality. Statin therapy had been suggested to attenuate recipient inflammation and immune response, potentially reducing the risk and severity of CLAD. This study aimed to evaluate the impact of statin use and in vivo exposure on the incidence of CLAD in lung transplant recipients (LTRs), as well as their effects on immune cells and inflammatory factors.

Methods

A retrospective cohort study was conducted on patients who underwent lung transplantation between January 2017 and December 2020. The incidence of CLAD, as per the 2019 ISHLT criteria, was assessed as the clinical outcome. The plasma concentrations of statin were measured using a validated UPLC-MS/MS method, while inflammation marker levels were determined using ELISA kits.

Results

The statin group exhibited a significantly lower rate of CLAD (P = 0.002). Patients receiving statin therapy showed lower CD4⁺ T-cell counts, total T-lymphocyte counts, and IL-6 levels (P = 0.017, P = 0.048, and P = 0.038, respectively). Among the CLAD groups, the atorvastatin level (2.51 ± 1.31 ng/ml) was significantly lower than that in the non-CLAD group (OR = 1.438, 95%CI (1.007–2.053), P = 0.046).

Conclusion

Statin therapy significantly reduced the incidence of CLAD, as well as immune cell counts and inflammatory cytokine levels in LTRs. Although the statin exposure was significantly lower in CLAD patients, it was not associated with the incidence of CLAD.

Purpose

Invasive fungal infections potentially result in fatal outcomes in immunocompromised hosts. Compared to intravenous administration, a nebulization therapy can achieve a high concentration of drug delivered in the respiratory tract, without a systematic absorption. We herein summarized the study findings on the safety and clinical utility of nebulized liposomal amphotericin B therapy.

Methods

According to the PRISMA Extension for Scoping Reviews, we performed a search on MEDLINE and EMBASE for articles with relevant keywords, including “inhaled liposomal amphotericin B″, “nebulized liposomal amphotericin B″, or “aerosolized liposomal amphotericin B″, from the inception of these databases to August 31, 2022.

Results

Of the 172 articles found, 27 articles, including 13 case reports, 11 observational studies, and 3 clinical trials, were selected. Generally, findings showed that nebulized liposomal amphotericin B treatment appeared to be safe and without severe adverse effects. We found an accumulated evidence for the safety, tolerability, and effectiveness of nebulized liposomal amphotericin B prophylaxis among lung transplantation recipients; however, a randomized controlled study has yet to be reported. Data on hemato-oncological patients are relatively scarce; however, a randomized controlled study suggested the prophylactic effect of nebulized liposomal amphotericin B on invasive pulmonary aspergillosis. Observational and randomized controlled studies to evaluate therapeutic efficacy of the nebulized liposomal amphotericin B therapy have not been performed.

Conclusion

In conclusion, we found increasing evidence for the effectiveness of the inhalation therapy among patients after lung transplantation and with hemato-oncological diseases.

This study investigates the molecular mechanism of FTO m6A demethylase in non-small cell lung cancer (NSCLC) and gefitinib resistance using GEO and TCGA databases. Differentially expressed genes (DEGs) were screened from RNA-seq data sets of serum exosomes of gefitinib-resistant NSCLC patients in the GEO database and the NSCLC data set in the GEPIA2 database. From this analysis, FTO m6A demethylase was found to be significantly upregulated in the serum exosomes of gefitinib-resistant NSCLC patients. To identify downstream genes affected by FTO m6A demethylase, weighted correlation network analysis and differential expression analysis were performed, resulting in the identification of three key downstream genes (FLRT3, PTGIS, and SIRPA). Using these genes, the authors constructed a prognostic risk assessment model. Patients with high-risk scores exhibited a significantly worse prognosis. The model could predict the prognosis of NSCLC with high accuracy measured by AUC values of 0.588, 0.608, and 0.603 at 1, 3, and 5 years respectively. Furthermore, m6A sites were found in FLRT3, PTGIS, and SIRPA genes, and FTO was significantly positively correlated with the expression of these downstream genes. Overall, FTO m6A demethylase promotes gefitinib resistance in NSCLC patients by upregulating downstream FLRT3, PTGIS, and SIRPA expression, with these three downstream genes serving as strong prognostic indicators.

The initial alterations of chronic obstructive pulmonary disease (COPD) involve the small airways. Small airway disease (SAD) is related to lung hyperinflation and air trapping. Several lung function tests may detect the presence of SAD, namely forced mid-expiratory flows, residual volume (RV), RV/total lung capacity (TLC) ratio, functional residual capacity, airway resistances obtained with body-plethysmography and oscillometry, and the single-breath nitrogen washout test. Additionally, high-resolution computed tomography can detect SAD. In addition to SAD, COPD is related to cardiovascular disease (CVD) such as heart failure, peripheral vascular disease, and ischemic heart disease. No studies have assessed the relationship between CVD, COPD, and SAD. Therefore, the main objective of the Assessing the Relationship between Cardiovascular and small Airway Disease and Acute events in COPD (ARCADIA) study is to assess the risk of CVD in COPD patients according to SAD in a real-life setting. The correlation between CVD, mortality, and acute exacerbation of COPD (AECOPD) is also evaluated.

ARCADIA is a 52-week prospective, multicentre, pilot, observational, cohort study conducted in ≥22 pulmonary centres in Italy and that enrols ≥500 COPD patients, regardless of disease severity (protocol registration: ISRCTN49392136). SAD is evaluated at baseline, after that CVD, mortality, and AECOPD are recorded at 6 and 12 months. Bayesian inference is used to quantify the risk and correlation of the investigated outcomes in COPD patients according to SAD.

The ARCADIA study provides relevant findings in the daily clinical management of COPD patients.

Background

The drug combination elexacaftor-tezacaftor-ivacaftor (ETI) proved highly effective in the improvement of the respiratory symptoms, the percentage of predicted forced expiratory volume in 1 s (FEV1), and to reduce rates of pulmonary exacerbations in people with cystic fibrosis (CF) with at least one F508del mutation.

The objectives of the study were to evaluate the impact of ETI on the daily treatment burden due to patient decision and the evolution of lung function parameters at 6 months of treatment in real life.

Methods

A single-center observational study was realized including adult patients starting ETI therapy from March 10, 2020 to April 5, 2022. Clinical characteristics were collected at initiation (T0) and at 6 months (T6) of treatment. Outcome measures included names and number of chronic daily medications, respectively lung function parameters: FEV1, forced vital capacity (FVC), FEV1/FVC ratio, peak expiratory flow (PEF), forced expiratory flow at 25–75% of FVC (FEF25-75), β‐angle and FEF50/PEF ratio.

Results

Sixty-five patients were included with a mean age of 29.4 ± 8.5 years old, 48% of them F508del homozygous previously treated by lumacaftor-ivacaftor. At T6, the median number of daily medications decreased from 13 [2-24] to 9 [1-19] (p < 0.001). All the studied functional respiratory parameters were improved: FEV1 +18%, FVC +14%, FEF25-75% + 18% (all p < 0.001), as well the airflow obstruction: FEV1/FVC +6%, FEF50/PEF by 0.1 ± 0.1 and β‐angle by 10° ± 13° (all p ≤ 0.007).

Conclusion

ETI therapy can reduce the daily treatment burden in real-life at 6 months of treatment, increase a large number of lung function parameters and improve airflow obstruction.

Hypoxic pulmonary hypertension (HPH) is a devastating disease worldwide; however, effective therapeutic drugs are lacking. This study investigated the effects and underlying mechanisms of LCZ696 treatment on hypoxia-induced pulmonary hypertension. Male Sprague-Dawley (SD) rats were kept in a hypobaric chamber with an oxygen concentration of 5% for 4 weeks. Rats were treated with either LCZ696 (18 mg/kg, 36 mg/kg, and 72 mg/kg) or sildenafil. The mean pulmonary artery pressure (mPAP), right ventricle hypertrophy index (RVHI), and lung system index were measured. Hematoxylin-eosin (HE) staining, Masson staining, and immunofluorescence staining were used for histological analysis. Enzyme linked immunosorbent assay (ELISA) kits were used to determine the concentrations of inflammatory and hypoxia-related factors. Western blotting was used to examine the expression of apoptotic and PI3K/AKT signaling pathway proteins in rat lung tissue. Hypoxia increased mPAP, RVHI, and lung system index and induced pulmonary vascular remodeling, pulmonary arteriomyosis, and pulmonary artery fibrosis. LCZ696 treatment reduced the increase in mPAP, RVHI, and the lung system index and ameliorated the induced pathological changes. Hypoxia upregulated expression of NF-kB, TNF-α, IL-6, HIF-1α, and Vascular endothelial growth factor (VEGF), decreased the ratio of Bax/Bcl-2, and activated the PI3K/AKT signaling pathway in lung tissue, and these effects were partially reversed by treatment with LCZ696. These results demonstrated that LCZ696 can ameliorate hypoxia-induced HPH by suppressing apoptosis, inhibiting the inflammatory response, and inhibiting the PI3K/AKT signaling pathway. It provides a reference for clinical rational drug use and lays a foundation for the study of HPH therapeutic drugs.

Objective

This study mainly analyzes the mechanism of SIRT3 alleviating sepsis-induced acute lung injury (ALI) by regulating the deacetylation of FoxO3a and inhibiting pyroptosis.

Methods

SIRT3-overexpressing and silenced BEAS-2B cells were used to evaluate the effect of SIRT3 on apoptosis in LPS-treated lung epithelial cells. FoxO3a-silenced BEAS-2B cells were also used to verify the mechanism by which SIRT3 inhibited oxidative stress and pyroptosis in vitro in ALI. 3-TYP was used to inhibit the deacetylation function of SIRT3 in vivo. Pyroptosis was assessed by detecting GSDMD-N and LDH efflux.

Results

In CLP-induced ALI mice, GSDMD-N and LDH levels were elevated, pyroptosis was induced. Silencing of SIRT3 exacerbated oxidative stress, NLRP3 activation and pyroptosis, and inhibited the deacetylation of FoxO3a. Overexpression of SIRT3 attenuated pyroptosis, induced deacetylation and restored the expression of FoxO3a and MnSOD. Silencing FoxO3a aggravated pyroptosis. Overexpression of SIRT3 restored the reduced FoxO3a expression and suppressed pyroptosis. 3-TYP blocked the promotion of FoxO3a by SIRT3 and the inhibitory effect of SIRT3 on pyroptosis.

Conclusion

The reduction of SIRT3 in sepsis caused hyperacetylation of FoxO3a, which in turn exacerbates oxidative stress and induces pyroptosis of ALI. Increasing the level of SIRT3 promotes FoxO3a through deacetylation, thereby inhibiting pyroptosis and relieving ALI.

Background

Bradykinin 1 receptor (B1R) signalling pathways may be involved in the inflammatory pathophysiology of chronic obstructive pulmonary disease (COPD). B1R signalling is induced by inflammatory stimuli or tissue injury and leads to activation and increased migration of pro-inflammatory cells. Lipopolysaccharide (LPS) lung challenge in man is an experimental method of exploring inflammation in the lung whereby interference in these pathways can help to assess pharmacologic interventions in COPD. BI 1026706, a potent B1R antagonist, was hypothesized to reduce the inflammatory activity after segmental lipopolysaccharide (LPS) challenge in humans due to decreased pulmonary cell influx.

Methods

In a monocentric, randomized, double-blind, placebo-controlled, parallel-group, phase I trial, 57 healthy, smoking subjects were treated for 28 days with either oral BI 1026706 100 mg bid or placebo. At day 21, turbo-inversion recovery magnitude magnetic resonance imaging (TIRM MRI) was performed. On the last day of treatment, pre-challenge bronchoalveolar lavage fluid (BAL) and biopsies were sampled, followed by segmental LPS challenge (40 endotoxin units/kg body weight) and saline control instillation in different lung lobes. Twenty-four hours later, TIRM MRI was performed, then BAL and biopsies were collected from the challenged segments. In BAL samples, cells were differentiated for neutrophil numbers as the primary endpoint. Other endpoints included assessment of safety, biomarkers in BAL (e.g. interleukin-8 [IL-8], albumin and total protein), B1R expression in lung biopsies and TIRM score by MRI as a measure for the extent of pulmonary oedema.

Results

After LPS, but not after saline, high numbers of inflammatory cells, predominantly neutrophils were observed in the airways. IL-8, albumin and total protein were also increased in BAL samples after LPS challenge as compared with saline control. There were no significant differences in cells or other biomarkers from BAL in volunteers treated with BI 1026706 compared with those treated with placebo. Unexpectedly, neutrophil numbers in BAL were 30% higher and MRI-derived extent of oedema was significantly higher with BI 1026706 treatment compared with placebo, 24 h after LPS challenge. Adverse events were mainly mild to moderate and not different between treatment groups.

Conclusions

Treatment with BI 1026706 for four weeks was safe and well-tolerated in healthy smoking subjects. BI 1026706 100 mg bid did not provide evidence for anti-inflammatory effects in the human bronchial LPS challenge model.

Trial registration

The study was registered on January 14, 2016 at ClinicalTrials.gov (NCT02657408).