Drugs For Chronic Obstructive Pulmonary Disease Research Articles

Therapeutic Targets and Precision Medicine in COPD: Inflammation, Ion Channels, Both, or Neither?

The development of a wider range of therapeutic options is a key objective in drug discovery for chronic obstructive pulmonary disease (COPD). Fundamental advances in lung biology have the potential to greatly expand the number of therapeutic targets in COPD. The recently reported successful Phase 3 clinical trial of the first biologic agent for COPD, the monoclonal antibody dupilumab, adds additional support to the importance of targeting inflammatory pathways in COPD. However, numerous other cellular mechanisms are important targets in COPD therapeutics, including airway remodeling, the CFTR ion channel, and mucociliary function. Some of these emerging targets can be exploited by the expanded use of existing COPD drugs, such as roflumilast, while targeting others will require the development of novel molecular entities. The identification of additional therapeutic targets and agents has the potential to greatly expand the value of using clinical and biomarker data to classify COPD into specific subsets, each of which can be predictive of an enhanced response to specific subset(s) of targeted therapies. The author reviews established and emerging drug targets in COPD and uses this as a framework to define a novel classification of COPD based on therapeutic targets. This novel classification has the potential to enhance precision medicine in COPD patient care and to accelerate clinical trials and pre-clinical drug discovery efforts.

Sevoflurane with Low Concentration Decrease DNA Methylation on Chronic Obstructive Pulmonary Disease (COPD)-Related Gene Promoter in COPD Rat

Chronic obstructive pulmonary disease (COPD) is a difficult-to-cure disease that mainly affects the respiratory system. Inhaled anesthetic drug such as sevoflurane plays a controversial role in COPD by different concentration, but the underlying epigenetic mechanism remains unclear. Here, we prepared lipopolysaccharide (LPS)-induced COPD rat model, and isolated Alveolar type II (ATII) cells. We mainly focused DNA methylation on the promoter of COPD-related genes including Sftpa1, Napsa, Ca2, Sfta2, Lamp3, Wif1, Pgc, and Etv5. We observed COPD rat treated by sevoflurane with low (0.5%) and high (2%) concentrations displayed an opposite DNA methylation pattern. These six genes' promoter were all hypomethylated by 0.5% sevoflurane whereas hypermethylated by 2% sevoflurane, accompanied with the opposite transcriptional activity. We further verified that the DNMT1 binding ability contributed to DNA methylation these six genes' promoter. Moreover, we also captured DNMT1 and identified REC8 meiotic recombination protein (REC8) as the specific binding protein only existed in ATII cells treated with 0.5% sevoflurane rather than 2% and control. The binding ability of REC8 on these target genes' promoter showed highly positive correlation with DNMT1. In summary, we uncovered a potential epigenetic role of sevoflurane with low concentration in ATII cells of COPD that may help us deeply understand the pathogenesis and treatment mechanism of inhaled anesthesia drugs in COPD via a dose-dependent manner.

Systematic analysis of various RNA transcripts and construction of biological regulatory networks at the post-transcriptional level for chronic obstructive pulmonary disease

BackgroundAlthough chronic inflammation, oxidative stress, airway remodeling, and protease-antiprotease imbalance have been implicated in chronic obstructive pulmonary disease (COPD), the exact pathogenesis is still obscure. Gene transcription and post-transcriptional regulation have been taken into account as key regulators of COPD occurrence and development. Identifying the hub genes and constructing biological regulatory networks at the post-transcriptional level will help extend current knowledge on COPD pathogenesis and develop potential drugs.MethodsAll lung tissues from non-smokers (n = 6), smokers without COPD (smokers, n = 7), and smokers with COPD (COPD, n = 7) were collected to detect messenger RNA (mRNA), microRNA (miRNA), circular RNA (circRNA), and long non-coding RNA (lncRNA) expression and identify the hub genes. Biological regulatory networks were constructed at the post-transcriptional level, including the RNA-binding protein (RBP)-hub gene interaction network and the competitive endogenous RNA (ceRNA) network. In addition, we assessed the composition and abundance of immune cells in COPD lung tissue and predicted potential therapeutic drugs for COPD. Finally, the hub genes were confirmed at both the RNA and protein levels.ResultsAmong the 20 participants, a total of 121169 mRNA transcripts, 1871 miRNA transcripts, 4244 circRNA transcripts, and 122130 lncRNA transcripts were detected. There were differences in the expression of 1561 mRNAs, 48 miRNAs, 33 circRNAs, and 545 lncRNAs between smokers and non-smokers, as well as 1289 mRNAs, 69 miRNAs, 32 circRNAs, and 433 lncRNAs between smokers and COPD patients. 18 hub genes were identified in COPD. TGF-β signaling and Wnt/β-catenin signaling may be involved in the development of COPD. Furthermore, the circRNA/lncRNA-miRNA-mRNA ceRNA networks and the RBP-hub gene interaction network were also constructed. Analysis of the immune cell infiltration level revealed that M2 macrophages and activated NK cells were increased in COPD lung tissues. Finally, we identified that the ITK inhibitor and oxybutynin chloride may be effective in treating COPD.ConclusionsWe identified several novel hub genes involved in COPD pathogenesis. TGF-β signaling and Wnt/β-catenin signaling were the most dysregulated pathways in COPD patients. Our study constructed post-transcriptional biological regulatory networks and predicted small-molecule drugs for the treatment of COPD, which enhanced the existing understanding of COPD pathogenesis and suggested an innovative direction for the therapeutic intervention of the disease.

Pathophysiology, Therapeutic Targets, and Future Therapeutic Alternatives in COPD: Focus on the Importance of the Cholinergic System

Chronic obstructive pulmonary disease (COPD) is a progressive disease characterized by airway limitation and changes in airway structure. It has a high global burden of mortality and morbidity. The etiology of COPD is complex, but exposure to tobacco smoke and other inhaled lung oxidants are major risk factors. Both pharmacological and non-pharmacological approaches are used to manage COPD, but there remains an urgent unmet need for drugs that can modify the course of the disease. This review focuses on the role of acetylcholine and other components of the pulmonary cholinergic system in the pathogenesis of COPD, and the inhaled pharmacological agents that target it. In addition to its role as a neurotransmitter, acetylcholine regulates diverse aspects of COPD pathogenesis including bronchoconstriction, airway remodeling, mucus secretion and inflammation. Inhaled antimuscarinic drugs are a key component of therapy for COPD, as monotherapy or in combination with inhaled β2 agonists or corticosteroids. We review the evidence supporting the use of current anticholinergic agents in COPD and preview novel drugs targeting the cholinergic system and agents from other classes in clinical development, such as phosphodiesterase-4 inhibitors and monoclonal antibodies targeting inflammatory mediators.

Potential of hydroethanolic leaf extract of Ocimum sanctum in ameliorating redox status and lung injury in COPD: an in vivo and in silico study

Oxidative stress and inflammation are hypothesised as the main contributor for Chronic Obstructive Pulmonary Disease (COPD). Cigarette smoke (CS), a major cause of COPD leads to inflammation resulting in recruitment of neutrophils and macrophages which are rich sources of oxidants. Activation of these cells produces excess oxidants and depletes antioxidants resulting in stress. Presently, effective drug for COPD is limited; therefore, novel compounds from natural sources, including plants are under exploration. The present study aims to investigate the protective effect of Ocimum sanctum leaf extract (OLE) in CS − induced model of COPD. Exposure to CS was performed thrice a week for 8 weeks and OLE (200 mg/kg and 400 mg/kg) was administered an hour before CS exposure. Control group (negative control) were exposed to ambient air while COPD group was exposed to CS (positive control). Administration of OLE doses reduced inflammation, decreased oxidant concentration and increased antioxidant concentration (p < 0.01). Molecular docking studies between the major phytocompounds of OLE (Eugenol, Cyclohexane and Caryophyllene) and antioxidant enzymes Superoxide dismutase (SOD), Catalase, Glutathione peroxidase (GPx), Glutathione reductase (GR) and Glutathione S Transferase (GST) showed strong binding interaction in terms of binding energy. In vivo and in silico findings for the first time indicates that OLE extract significantly alleviates oxidative stress by its potent free radical scavenging property and strong interaction with antioxidant enzymes. OLE extract may prove to be a therapeutic option for COPD prevention and treatment.

Clinical factors linked to the type of respiratory medication in COPD: results from the COSYCONET cohort.

The use of maintenance medication in patients with chronic obstructive pulmonary disease (COPD) in real life is known to deviate from recommendations in guidelines, which are largely based on randomized controlled trials and selected populations. We used the COSYCONET (COPD and Systemic Consequences - Comorbidities Network) cohort to analyze factors linked to the use of COPD drugs under non-interventional circumstances. COSYCONET is an ongoing, multi-center, non-interventional cohort of patients with COPD. Patients with COPD of Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades 0-4 participating in visits 1-5 were included. Data covered the period from 2010 to 2018. Generalized linear models were used to examine the relation of COPD characteristics to different types of respiratory medication. A total of 1043 patients were included. The duration of observation was 4.5 years. Use of respiratory medication depended on GOLD grades 0-4 and groups A-D. Long-acting muscarinic antagonist therapy increased over time, and was associated with low carbon monoxide (CO) diffusing capacity, while inhaled corticosteroid (ICS) use decreased. Active smoking was associated with less maintenance therapy in general, and female sex with less ICS use. From the eight items of the COPD Assessment Test, only hill and stair climbing were consistently linked to treatment. Using data from a large, close to real-life observational cohort, we identified factors linked to the use of various types of respiratory COPD medication. Overall, use was consistent with GOLD recommendations. Beyond this, we identified other correlates of medication use that may help us to understand and improve therapy decisions in clinical practice. ClinicalTrials.gov NCT01245933.

Assessment of the Medication Adherence Among Chronic Obstructive Pulmonary Disease Patients in ALSha’ab Teaching Hospital, Sudan

Background: Adherence to therapy is one of the basic predilections to successfully treating chronic obstructive pulmonary disease (COPD). Unfortunately, predictors of medication adherence are not well-known in chronic obstructive pulmonary disease (COPD) in Sudan. Objective: To assess the medication adherence in the patients treated for COPD in ALSha’ab Teaching Hospital. Methods: An observational, hospital-based cross-sectional study conducted on a sample of COPD outpatients. The following information was obtained: adherence to COPD therapy (Morisky Medication Adherence Scale - 4 items), age, gender, smoking status, treatment regimen for COPD, and COPD medication costs per month paid by the patients. Data was analyzed by using SPSS version 21.0. Results: Among 100 COPD patients, 73 (73%) were males, and (47%) belonged to the age group 40- 60 years. Regarding adherence, 47 (47%) reported as medium adherent, 38 (38%) as low adherents, and 15 (15%) patients as high adherent. High Adherence to COPD therapy was associated with older age (27%), married (16.5%), literate (23.3%), drugs with less frequent dosing (50%), oral medications (75%), aware of the inhaler usage (22.7%), a smaller number of drugs (41.4%), and affordable drugs (28.8%). Conclusion: The level of adherence to COPD therapy is low. Understanding factors associated with medication adherence could help enhance health outcomes in COPD. Non-adherence was associated with middle age, unmarried patients, number of respiratory drugs and daily COPD drug doses, Low knowledge and increased difficulties in inhaler technique, and non-affordability of drugs.

Associations of medication regimen complexity with medication adherence and clinical outcomes in patients with chronic obstructive pulmonary disease: a prospective study.

High medication burdens are common in patients with chronic obstructive pulmonary disease (COPD). This study aimed to explore the associations of medication regimen complexity index (MRCI) with medication adherence and clinical outcomes among patients with acute exacerbations of COPD (AECOPD) after hospital discharge. Data were obtained from a nationwide cohort study of inpatients with AECOPD in China. MRCI scores were calculated using the medication list 30 days after discharge and separated into COPD-specific and non-COPD MRCI scores. Medication adherence was measured by the withdrawal rate of COPD or inhaled long-acting bronchodilators 6 months after discharge. Clinical outcomes included re-exacerbations and COPD-related readmissions during the 30-day to 6-month follow-up period. The associations of MRCI with medication withdrawal and clinical outcomes were evaluated using univariate and multivariate logistic regressions. Potential covariates included sociodemographic factors, year of COPD diagnosis, post-bronchodilator percentage predicted forced expiratory volume in 1 s, mMRC score, CAT score, and comorbidities. Among the 2853 patients included, the median total MRCI score was 7 [interquartile range (IQR), 7-13]. A high MRCI score (>7) was presented in 1316 patients (46.1%). Of the MRCI score, 91% were COPD specific. The withdrawal rates of the COPD and inhaled long-acting bronchodilators were 24.2% and 24.4%, respectively. Re-exacerbation and COPD-related readmission rates were 10.2% and 7.5%, respectively. After adjusting for covariates, patients with high total MRCI scores were less likely to discontinue COPD drugs [odds ratio (OR), 0.62; 95% confidence interval (CI), 0.52-0.74] and inhaled long-acting bronchodilators (OR, 0.68; 95%CI, 0.57-0.81); conversely, these patients were more likely to experience re-exacerbation (OR, 1.64; 95% CI, 1.27-2.11) and readmission (OR, 1.57; 95% CI, 1.17-2.10). MRCI scores were relatively low among post-hospitalized patients with AECOPD in China. Higher MRCI scores were positively associated with adherence to COPD or inhaled medications, and risk of re-exacerbation and readmission. ClinicalTrials.gov identifier: NCT02657525.

Chinese expert consensus on the management of cardiovascular comorbidities in patients with chronic obstructive pulmonary disease

Patients with chronic obstructive pulmonary disease(COPD) often have co-existent systemic diseases(comorbidities), among which cardiovascular diseases (CVD) are the most common. The interactions between COPD and CVD are manifested in shared risk factors, disease severity, common symptoms, risks for exacerbations and disease progression, as well as therapeutic interventions. However, there is a knowledge gap in the management of COPD comorbidities. This expert consensus aims to increase the awareness, and to promote early diagnosis and proper management of cardiovascular comorbidities of COPD in medical professionals in China. The experts recommend that differential diagnosis should be performed for exertional dyspnea, a common symptom of COPD and cardiovascular diseases especially heart failure. Screening for cardiovascular diseases is needed in patients with COPD, and should be managed accordingly. COPD and comorbid CVD should be treated according to usual guidelines. Patients with COPD tolerate well to most of the medications for CVD. Selective β1-blockers for cardiovascular diseases are not contraindicated in COPD, but should be initiated from lower doses, and symptoms of airflow limitation be monitored. Likewise, β2-agonists and antimuscarinic drugs for COPD are generally safe for patients with comorbid CVD. Optimization of COPD management can improve heart function and cardiovascular outcomes.

Design and synthesis of 2-(2,2-diarylethyl)-cyclamine derivatives as M3 receptor antagonists and functional evaluation on COPD

Muscarine acetylcholine receptors (mAChRs) regulate a variety of central and peripheral physiological functions and emerge as important therapeutic targets for a number of diseases including chronic obstructive pulmonary disease (COPD). Inspired by two active natural products, we designed and synthesized a series of 2-(2,2-diarylethyl)-cyclamine derivatives for screening M3 mAChR antagonists. On this skeleton, the structural units including N heterocycle, aryl groups and its substituents on aryl were examined and resulted in a clear structure–activity relationships on the M3 mAChR. In general, these 2-(2,2-diarylethyl)-cyclamine derivatives exhibited good to excellent M3 antagonistic potency and receptor selectivity. The most active 5b-C1 had an IC50 value of 3 nM and the most of compound 6 displayed inactivity against histamine H1 receptor closely related to M3. In in vitro and in vivo evaluations of tracheo-relaxation function, some compounds even showed comparable activity to tiotropium bromide, a known blockbuster drug for COPD. Such excellent properties made these novel compounds potential candidates for COPD drug development.

Expert consensus on physician-pharmacist collaborative management of stable chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a common chronic airway disease. COPD patients need lifelong treatment, and long-term standardized inhalation medication is the core of stable COPD drug therapy. But, in the process of COPD stabilization management, the use accuracy rate of inhalation device is low and compliance is poor, and in addition, chronic diseases such as ischemic heart disease, heart failure, hypertension and diabetes are common in COPD patients, and these complications often involve multiple medications, which have potential drug risks associated with drug interactions that affect patient outcomes. Based on the experience of pharmacists involved in the management of other chronic diseases, experts from Respiratory Equipment Technical Committee of China Association of Medical Equipment, jointly with Chronic Obstructive Pulmonary Disease Group of Chinese Thoracic Society and Guangdong Pharmaceutical Association, developed expert consensus on physician-pharmacist collaborative management of stable chronic obstructive pulmonary disease, aiming to improve patients' treatment compliance and satisfaction, reduce the acute attack rate, and ultimately improve the treatment level of COPD.

Pathological Mechanism and Targeted Drugs of COPD.

Chronic obstructive pulmonary disease (COPD) includes chronic bronchitis, emphysema, and small airway obstruction. Incompletely reversible airflow limitation, inflammation, excessive mucus secretion and bronchial mucosal epithelial lesions are the main pathological basis of the disease. The prevalence of COPD is increasingly worldwide, which has caused the burden on individuals and society. This paper summarizes the pathogenesis of COPD and clarifies the effect and mechanism of the latest targeted drugs for COPD. Besides, we focus on NOD-like receptor thermal protein domain associated protein 3 inflammasome (NLRP3 inflammasome). NLRP3 can promote production of interleukin-1β (IL-1β) and interleukin-18 (IL-18). NLRP3 is an important factor in the migratory aggregation of macrophages and neutrophils and the generation of oxidative stress. Inhibition of NLRP3 inflammasome indirectly blocks the inflammatory effects of IL-1β and IL-18, which may be regarded as an ideal target for COPD treatment.

Sustained Release Theophylline (SRT): An Older Drug for COPD which Still Retains its Edge in the Management of this Chronic Disease

Sustained release theophylline (SRT) has been an important component in the Pharmacotherapy of Chronic Obstructive Pulmonary Disease (COPD). Recent years have witnessed a dynamic change in the treatment of this disease. Several new drugs, especially inhaled ones, have largely supplanted the oral drugs used in COPD. SRT has also been relegated to such a position that it is an option which may be used in very severe cases only on the Clinician’s discretion. The axiom that development of new drugs does not belittle the clinical edge of the previous used one is in our opinion applicable to SRT. In this abstract, we attempt to underline the importance of Sustained-Released Theophylline (SRT) in the management of COPD.The endeavour is to systematically emphasize the myriad actions of SRT which provide relief by multiple means to patients in Acute exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD).

Prevalence of Pharmacologic Treatments for Chronic Obstructive Pulmonary Disease in Relation of Diagnosis of Dementia Among Nursing Homes Residents.

Chronic obstructive pulmonary disease (COPD) is a chronic disease affecting millions of older adults. We investigated the prevalence of nursing home (NH) residents with COPD and their pharmacologic treatment in relation to the diagnosis of dementia and the prevalence of potentially severe drug-drug interactions (DDIs) of COPD medications with drugs prescribed to treat comorbidities. Retrospective cross-sectional multicentre study. Individuals living in long-term care NHs. This cross-sectional cohort study was conducted in a sample of Italian long-term care NHs located throughout the country. Information on drug prescriptions, diseases, and sociodemographic characteristics was collected using medical records between 2018 and 2020. Potentially severe DDIs were analyzed using INTERCheck, developed by the Istituto di Ricerche Farmacologiche Mario Negri IRCCS. Among the 2604 residents living in 27 NHs (mean age 86.4 ± 8.5years; women 1995, 76.6%; number of drugs 7.3 ± 3.6), 306 had a diagnosis of COPD (11.8%) and 84 (27.5%) of them were treated with at least 1 medication for COPD (27.5%). Those without dementia had a higher prevalence of drugs for COPD than those with dementia (48% vs 20%, P < .0001). The most used classes for COPD were adrenergics in combination with corticosteroids (16.7%) and inhalant anticholinergics (14.7%). Among those receiving medications for COPD, 45 had at least 1 potentially severe DDI with medications for comorbidities (53.6%) and most of them were associated with an increased risk of QTc prolongation, as beta2 agonists with diuretics, antipsychotics or antidepressants. Most NH residents with COPD did not receive any medication for this disease despite the potential benefits. Residents with dementia received fewer COPD medications probably because of their compromised physical and cognitive status. One-half of the NH residents taking medication for COPD were exposed to an increased risk of QTc prolongation and torsades de pointe because of pharmacodynamic DDIs with medication for comorbidities. Close monitoring of electrocardiograms for NH residents with COPD is recommended.

Current status of interventional therapy for pulmonary emphysema with bronchoscopy.

Pulmonary emphysema is one of phenotypes of lung disease that can progress to chronic obstructive pulmonary disease (COPD). The pathogenesis is unknown, which may be closely related to smoking, infection, gene mutation, and air pollution. Pathological features of emphysema include the decreased airway elasticity at the distal end of the bronchioles and over-hyperinflation. As the incidence and mortality of COPD increase, emphysema has become the focus of research. The efficacy of drugs for COPD is limited, and currently the treatment of emphysema mainly depends on surgery. Since the concept of lung volume reduction surgery was proposed in the 1990s, many studies have confirmed improvement of lung function and exercise capacity, but the large wound, high mortality, and high cost have reduced its benefits. Lung volume reduction surgery with bronchoscopy technology, including valves, coils, sclerosants, vapor thermal ablation, etc., has the advantages of minimal invasive and decreased mortality under the basis of effectiveness. This article aims to review the current status of interventional therapy for pulmonary emphysema with bronchoscopy, compare and summarize the characteristics and applicable populations of interventional therapy, and provide theoretical support for patients' early referral and clinicians' decision-making.

Proteomic Network Analysis of Bronchoalveolar Lavage Fluid in Ex-Smokers to Discover Implicated Protein Targets and Novel Drug Treatments for Chronic Obstructive Pulmonary Disease.

Bronchoalveolar lavage of the epithelial lining fluid (BALF) can sample the profound changes in the airway lumen milieu prevalent in chronic obstructive pulmonary disease (COPD). We compared the BALF proteome of ex-smokers with moderate COPD who are not in exacerbation status to non-smoking healthy control subjects and applied proteome-scale translational bioinformatics approaches to identify potential therapeutic protein targets and drugs that modulate these proteins for the treatment of COPD. Proteomic profiles of BALF were obtained from (1) never-smoker control subjects with normal lung function (n = 10) or (2) individuals with stable moderate (GOLD stage 2, FEV1 50–80% predicted, FEV1/FVC < 0.70) COPD who were ex-smokers for at least 1 year (n = 10). After identifying potential crucial hub proteins, drug–proteome interaction signatures were ranked by the computational analysis of novel drug opportunities (CANDO) platform for multiscale therapeutic discovery to identify potentially repurposable drugs. Subsequently, a literature-based knowledge graph was utilized to rank combinations of drugs that most likely ameliorate inflammatory processes. Proteomic network analysis demonstrated that 233 of the >1800 proteins identified in the BALF were significantly differentially expressed in COPD versus control. Functional annotation of the differentially expressed proteins was used to detail canonical pathways containing the differential expressed proteins. Topological network analysis demonstrated that four putative proteins act as central node proteins in COPD. The drugs with the most similar interaction signatures to approved COPD drugs were extracted with the CANDO platform. The drugs identified using CANDO were subsequently analyzed using a knowledge-based technique to determine an optimal two-drug combination that had the most appropriate effect on the central node proteins. Network analysis of the BALF proteome identified critical targets that have critical roles in modulating COPD pathogenesis, for which we identified several drugs that could be repurposed to treat COPD using a multiscale shotgun drug discovery approach.

Vitex negundo L. derived specialized molecules unveil the multi-targeted therapeutic avenues against COPD: a systems pharmacology approach.

Chronic obstructive pulmonary disease (COPD) is an inflammatory disease caused by increasing breathing passage obstruction which completely disrupts human homeostasis. Some patients require lung transplantation or long-term oxygen therapy. COPD is one of the noxious diseases and its fourth leading cause of death around the globe. There is an immediate need for potential drug development to tackle this serious disease. Folk medicines are used to combat complex diseases that have shown effectiveness in the treatment of breathing diseases. Vitex negundo L. is an ethnobotanically important medicinal plant used for various ailments and modulates human cellular events. This shrub has diverse specialized metabolites and is being used as complementary medicine in various countries. Though systems-level understanding is there on the mode of action, the multi-target treatment strategy for COPD is still a bottleneck. In this investigation, systems pharmacology, cheminformatics, and molecular docking analyses were performed to unravel the multi-targeted mechanisms of V. negundo L. potential bioactives to combat COPD. Cheminformatics analysis combined with the target mining process identified 86 specialized metabolites and their corresponding 1300 direct human receptors, which were further imputed and validated systematically. Furthermore, molecular docking approaches were employed to evaluate the potential activity of identified potential compounds. In addition, pharmacological features of these bioactives were compared with available COPD drugs to recognize potential compounds that were found to be more efficacious with higher bioactive scores. The present study unravels the druggable targets and identifies the bioactive compounds present in V. negundo L., that may be utilized for potential treatment against COPD. However, further in vivo analyses and clinical trials of these molecules are essential to deciphering their efficacy.

Assessment of the predictive capability of modelling and simulation to determine bioequivalence of inhaled drugs: A systematic review.

There are a multitude of different modelling techniques that have been used for inhaled drugs. The main objective of this review was to conduct an exhaustive survey of published mathematical models in the area of asthma and chronic obstructive pulmonary disease (COPD) for inhalation drugs. Additionally, this review will attempt to assess the applicability of these models to assess bioequivalence (BE) of orally inhaled products (OIPs). PubMed, Science Direct, Web of Science, and Scopus databases were searched from 1996 to 2020, to find studies that described mathematical models used for inhaled drugs in asthma/COPD. 50 articles were finally included in this systematic review. This research identified 22 articles on in silico aerosol deposition models, 20 articles related to population pharmacokinetics and 8 articles on physiologically based pharmacokinetic modelling (PBPK) modelling for inhaled drugs in asthma/COPD. Among all the aerosol deposition models, computational fluid dynamics (CFD) simulations are more likely to predict regional aerosol deposition pattern in human respiratory tracts. Across the population PK articles, body weight, gender, age and smoking status were the most common covariates that were found to be significant. Further, limited published PBPK models reported approximately 29 parameters relevant for absorption and distribution of inhaled drugs. The strengths and weaknesses of each modelling technique has also been reviewed. Overall, while there are different modelling techniques that have been used for inhaled drugs in asthma and COPD, there is very limited application of these models for assessment of bioequivalence of OIPs. This review also provides a ready reference of various parameters that have been considered in various models which will aid in evaluation if one model or hybrid in silico models need to be considered when assessing bioequivalence of OIPs.

Management of Psychiatric Disorders in Patients with Respiratory Diseases.

Management of Psychiatric Disorders in Patients with Respiratory Diseases.

Abstract 13740: QT Interval-Prolonging Drugs May Influence Risk for Sudden Cardiac Death in Patients With Chronic Obstructive Pulmonary Disease

Background: QT-prolonging drugs have been shown to increase risk of sudden cardiac death (SCD). Here we aimed to identify comorbidities that may influence risk for SCD when taking specific types of QT-prolonging drugs. Methods: From the ongoing Oregon Sudden Unexpected Death Study (ORESUDS), we identified individuals with SCD and geographically-matched control subjects (2002 – 2016) with pre-arrest medical history and data on current medication use (at the time of arrest for cases). QT prolonging drugs were categorized according to the four risk categories defined by crediblemeds.com (referred to as A (Known risk), B (Possible risk), C (Conditional risk), and D (Risk of TdP in congenital LQTS). We utilized multivariable logistic regression models with backwards stepwise selection to identify significant comorbidities and QT risk categories or drug types associated with SCD. Models were adjusted for age, sex, history of MI, diabetes, congestive heart failure, hypertension, renal insufficiency, history of epilepsy, chronic obstructive pulmonary disease (COPD), and asthma. We evaluated two-way interactions between QT drugs and comorbidities. Results: A total of 2,813 cases (64% male, mean age 67 years) and 1,547 controls (66% male, mean age 65 years) were included. After variable selection, COPD, among other clinical profile variables, was significantly associated with SCD (OR 3.00, 95% CI 1.99 to 4.64). QT type D drugs were negatively associated with SCD (OR .39, 95% CI .30 to .50), whereas type A drugs were associated with significantly increased risk of SCD (OR 1.48, 95% CI 1.17 to 1.89). Two interactions between COPD and QT drug classes were observed. In one, the negative association of type D drugs with SCD was significantly attenuated in patients with COPD due to a positive interaction (interaction OR 1.90, 95% CI 1.19 to 3.04, p = .007). In the other, a stronger positive association with SCD was observed in patients with COPD taking type A drugs but not type D drugs (interaction OR 2.25, 95% CI .85 to 7.78, p = .14). Conclusion: These findings suggest the need for careful assessment of risk vs. benefit while considering QT-prolonging agents in patients with COPD. Further investigation is needed on the potential contribution of these agents on risk of SCD in COPD.