Pulmonary pharmacology & therapeutics最新文献

COVID-19 medicines, such as molnupiravir are beginning to emerge for public health and clinical practice. On the other hand, drugs display marked variability in their efficacy and safety. Hence, COVID-19 medicines, as with all drugs, will be subject to the age-old maxim “one size prescription does not fit all”. In this context, pharmacogenomics is the study of genome-by-drug interactions and offers insights on mechanisms of patient-to-patient and between-population variations in drug efficacy and safety. Pharmacogenomics information is crucial to tailoring the patients' prescriptions to achieve COVID-19 preventive and therapeutic interventions that take into account the host biology, patients’ genome, and variable environmental exposures that collectively influence drug efficacy and safety. This expert review critically evaluates and summarizes the pharmacogenomics and personalized medicine aspects of the emerging COVID-19 drugs, and other selected drug interventions deployed to date. Here, we aim to sort out the hope, hype, and reality and suggest that there are veritable prospects to advance COVID-19 medicines for public health benefits, provided that pharmacogenomics is considered and implemented adequately. Pharmacogenomics is an integral part of rational and evidence-based medical practice. Scientists, health care professionals, pharmacists, pharmacovigilance practitioners, and importantly, patients stand to benefit by expanding the current pandemic response toolbox by the science of pharmacogenomics, and its applications in COVID-19 medicines and clinical trials.

Background

Asthma is an inflammatory syndrome characterized by airway hyperresponsiveness, bronchial inflammation, and airway remodeling. Abnormal proliferation of airway smooth muscle cells (ASMCs) is the main pathological feature of asthma. This study investigated the function and mechanism of serine arginine-rich splicing factor 1 (SRSF1) in ASMC proliferation in asthma.

Methods

SRSF1 expressions in the bronchi of ovalbumin-induced asthmatic mice and IgE-treated mouse ASMCs (mASMCs) were evaluated using quantitative real-time PCR and Western blot. The localization and expression of SRSF1 in the bronchi of asthmatic mice were assessed by immunohistochemistry. Functionally, gain- and loss-of-function assays, flow cytometry, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays were conducted. Mechanistically, RNA degradation assay, RNA immunoprecipitation, RNA pull-down, and dual-luciferase reporter gene assays were carried out.

Results

SRSF1 was highly expressed in the bronchi of ovalbumin-induced asthma mice and IgE-treated mASMCs and was mainly located in the nucleus. Experiments on the function of SRSF1 showed that the silencing of SRSF1 induced the cell cycle of mASMC arrest and restrained mASMC proliferation. Investigations into the mechanism of SRSF1 revealed that SRSF1 and miR-135a are competitively bound to the 3′UTR region of Cyclin D2 (CCND2). SRSF1 overexpression repressed the degradation of CCND2 mRNA, and miR-135a negatively regulated CCND2 expression. Furthermore, SRSF1 knockdown inhibited ASMC proliferation in asthma mouse models by regulating the levels of miR-135a and CCND2.

Conclusion

SRSF1 knockdown repressed ASMC proliferation in asthma by regulating miR-135a/CCND2 levels.

Increased oxidative stress and high uric acid are implicated in the pathogenesis of pulmonary hypertension (PH). This provides opportunity to benefit from drugs like allopurinol which suppresses both contributing factors. Therefore, we aimed to investigate the effects of allopurinol in preventing as well as reversing the pathological changes occurring in monocrotaline (MCT)-induced rat model of PH. Male rats were assigned into three groups based on the follow-up time: 7, 21 and 35 days. Time-matched controls of each group received single injections of MCT (60 mg/kg) intraperitoneally. Test groups consisted of rats who were treated with MCT on day 0 plus oral allopurinol (60 mg/kg) daily for 7 or 21 days. 35-day group received allopurinol for two weeks starting on the 22nd day following MCT injection. At the end of all-time points, rats were killed and basal pulmonary perfusion pressure, Fulton index, pulmonary arterial wall thickness and pulmonary arterial relaxations along with oxidative stress markers (MDA, SOD, XO), NO and uric acid levels were measured in all groups. MCT-injected rats had evidence of raised oxidative stress (high MDA and XO, low SOD levels) which was reversed by allopurinol co-treatment in all-time groups. Marked elevation of uric acid seen in 21- and 35 day-groups was also reversed by allopurinol. Reduced NO levels of 21 and 35 days were unchanged in allopurinol treated groups. Apart from an increase in arterial wall thickening which was maintained in all-time groups, no alterations in other cardiovascular parameters were observed in 7-day group. However, basal lung perfusion pressure and Fulton index significantly increased, while arterial relaxations decreased in 21- and 35-day groups. Co-treatment with allopurinol for 21 days improved these functional alterations, whereas late allopurinol treatment failed to affect them. Our results indicate that early treatment of MCT-induced PH with allopurinol ameliorated the impaired functional characteristics via suppressing the increased oxidative stress and uric acid, while treatment started after progression of the disease had no significant effect.

Respiratory viral infections are the leading cause of death worldwide. The current pandemic of coronavirus infection (COVID-19) challenged human beings for the treatment and prevention of this respiratory viral infection since its outbreak in 2019. Despite advancements in the medical field, scientists were helpless to give timely treatment and protection against this viral infection. Several drugs, whether antiviral or not, were given to the patients to reduce mortality and morbidity rate. Vaccines from various pharmaceutical manufacturers are now available to give immunization against covid-19. Still, coronavirus is continuously affecting people in the form of variants after mutation. Each new variant increases the infection risk and forces scientists to develop some innovative and effective treatments for this infection. The virus uses the host's cell machinery to grow and multiply in numbers. Therefore, scientists are facing challenges to develop antivirals that stop the virus without damaging the host cells too. The production of suitable antivirals or vaccines for the new virus would take several months, allowing the strain to cause severe damage to life. Inhalable formulation facilitates the delivery of medicinal products directly to the respiratory system without causing unwanted side effects associated with systemic absorption. Scientists are focusing on developing an inhaled version of the existing antivirals for the treatment of respiratory infections. This review focused on the inhalable formulations of antiviral agents in various respiratory viral infections including the ongoing covid-19 pandemic and important findings of the clinical studies. We also reviewed repurposed drugs that have been given through inhalation in covid-19 infection.

Introduction

Loss of bronchoprotection against direct and indirect acting stimuli following regular use of inhaled beta₂-agonists occurs with both short and long-acting formulations. Comparatively little is known about the development of tolerance following regular use of inhaled muscarinic receptor antagonists. Two investigations with the short-acting muscarinic receptor antagonist ipratropium bromide have reported no tolerance after regular use against inhaled methacholine. To our knowledge, there are no data regarding loss of bronchoprotection following regular use of long-acting muscarinic receptor antagonist. We therefore looked at the effect of daily dosing with tiotropium on methacholine induced bronchoconstriction in a population of mild asthmatics.

Methods

We performed a randomized, double-blind, placebo-controlled cross-over study comparing tiotropium Respimat® 5 μg to placebo in adult asthmatics. Each treatment arm began with baseline methacholine challenge followed immediately by treatment administration. One hour later a post treatment methacholine challenge was performed. Participants dosed daily (two puffs) at home for the next six days and returned to the lab on Day 8 for a final dose of treatment 1 h prior to methacholine challenge.

Results

The average doubling dose increase in methacholine PD₂₀ following a single dose of tiotropium was 3.9 doubling doses whereas that following placebo was 0.93 (p = 0.003). After regular use, methacholine PD₂₀ was further increased to 6.4 doubling doses following tiotropium whereas that following placebo decreased by 0.57 doubling doses (p < 0.001).

Conclusion

LAMA are indicated for use as add-on monotherapy or in triple therapy combination for poorly controlled asthma. It may be reassuring to know therefore, that regular use does not result in loss of bronchoprotection like that which occurs with beta₂-agonist bronchodilators.

Cryptogenic organizing pneumonia is a diffuse interstitial lung disease that starts in the alveolar wall and subsequently expands to the alveolar ducts and respiratory bronchioles. Randomized controlled trials are lacking to guide the treatment of cryptogenic organizing pneumonia, so treatment decisions and practice guidelines are often based upon observations from case series or expert clinical opinions. The backbone of treatment involves immunosuppression via corticosteroids. In refractory cases, cytotoxic therapy is considered. The evidence that supports the use of these regimens are limited. The goal of this scoping review is to conduct a systematic search of the literature to determine what regimens have been utilized to treat steroid refractory organizing pneumonia and to characterize the evidence supporting their use.