Cilomilast: a second generation phosphodiesterase 4 inhibitor for asthma and chronic obstructive pulmonary disease

Cilomilast (Ariflo^? , SB-207499) is an orally-active, second generation phosphodiesterase (PDE) inhibitor that may be effective in the treatment of asthma and chronic obstructive pulmonary disease (COPD). It has high selectivity for the cyclic AMP-specific, or PDE4, isoenzyme that predominates in pro-inflammatory and immune cells and is ten-fold more selective for PDE4D than for PDE4A, B and C. In vitro, cilomilast suppresses the activity of many pro-inflammatory and immune cells that have been implicated in the pathogenesis of asthma and COPD and is highly active in animal models of these diseases. Cilomilast demonstrates a markedly improved side effect profile over the archetypal PDE4 inhibitor, rolipram, which has been attributed to its inability to discriminate between the high affinity rolipram binding site and the catalytic domain of the enzyme, and the fact that it is negatively charged which at physiological pH should limit its penetration in to the CNS. In humans cilomilast is rapidly absorbed after oral administration, providing dose-proportional systemic exposure up to 4 mg, completely bioavailable, has a half-life of ~ 7 h and is subject to negligible first pass hepatic metabolism. Cilomilast is extensively metabolised with decyclopentylation, acyl glucuronidation and 3-hydroxylation of the cyclopentyl ring representing the principal routes. Most of the drug is excreted in the urine (~ 90%) and faeces (6 - 7%) with unchanged cilomilast accounting for less than 1% of the administered dose. Cilomilast has been evaluated in Phase I, Phase II and Phase III trials and dose-response experiments have demonstrated a clinically significant increase in lung function and a perceived improvement in quality of life in patients with COPD. Trials of cilomilast in asthma have been less impressive although a trend towards improved lung function has been reported. Cilomilast is safe and well-tolerated at doses up to 15 mg in both short- and long-term dosing trials with a low incidence of adverse effects. No evidence for drug-drug interactions with commonly prescribed medications for COPD and asthma such as digoxin, corticosteroids, salbutamol, theophylline or warfarin has been found. Moreover, the pharmacokinetics of cilomilast are essentially the same in smokers and non-smokers, indicating that no dose adjustments of cilomilast will be required in patients with COPD. Thus, cilomilast displays a promising clinical profile in the treatment of inflammatory airway diseases, in particular COPD and the results of further Phase III trials are awaited with interest.     

吸入制剂在哮喘和慢性阻塞性肺疾病治疗中的作用及地位

在欧美等发达国家哮喘与慢性阻塞性肺疾病(COPD)患者普遍使用吸入制剂,我国大陆地区吸入制剂的应用尚未得到广泛推广,同时还面临着定量吸入气雾剂抛射剂氟利昂淘汰的困境。本文综述哮喘与COPD治疗中常用的吸入制剂,及其与非吸入制剂相比不可替代的临床地位。     

Targeting systemic inflammation: novel therapies for the treatment of chronic obstructive pulmonary disease

The increasing evidence that inflammation in the lungs leads to the structural changes observed in chronic obstructive pulmonary disease, whereas extrapulmonary symptoms and comorbidities may be systemic manifestations of these inflammatory processes, highlights an urgent need to discover novel, effective anti-inflammatory treatments for this disease. Some studies are suggesting that, by decreasing dynamic hyperinflation, bronchodilators might reduce systemic inflammation; inhaled corticosteroids and their combination with long-acting β₂-agonists might contribute to this goal. Even so, the opinion that suppression of the inflammatory response might improve systemic complications is stimulating a search for novel anti-inflammatory therapies. Many drugs include those that inhibit the recruitment and activation of inflammatory cells and/or antagonise their products. However, many of these therapeutic strategies are not specific for neutrophilic inflammation because they affect other cell types, thus, it is difficult to interpret whether any clinical benefit observed is a result of a reduction in airway neutrophils. In any case, there is some evidence that drugs used to treat a co-morbid condition, such as statins, angiotensin converting enzyme (ACE) inhibitors and angiontensin II type 1 (AT1) receptor blockers as well as glycosaminoglycans and peroxisome proliferator-activated receptor (PPAR) agonists, might benefit chronic obstructive pulmonary disease patients because they deal with the extrapulmonary, systemic component of chronic obstructive pulmonary disease.     

New anti-inflammatory therapies and targets for asthma and chronic obstructive pulmonary disease

Asthma and chronic obstructive pulmonary disease (COPD) are diseases of the airways with an underlying inflammatory component. The prevalence and healthcare burden of asthma and COPD is still rising and is predicted to continue to rise in the foreseeable future. β-agonists and corticosteroids form the basis of the therapies available to treat asthma. However, the treatments available for COPD, corticosteroids and anticholinergics, reduce the number and severity of exacerbations, but have a limited effect on slowing the progression of the disease. The inflammatory processes underlying the pathology of asthma have received a great deal of attention and more recently, those underlying COPD have begun to be elucidated. This has resulted in the identification of new targets that will allow the development of novel approaches by the pharmaceutical industry, which will be able to focus its efforts in an attempt to provide new and improved therapies to treat these debilitating diseases. The resultant therapies should impinge on the underlying development of these diseases rather than providing symptomatic relief or palliative treatment alone. This review will outline new targets and novel approaches currently under investigation, which may provide opportunities for novel anti-inflammatory therapeutic interventions that slow or halt disease progression in asthma and COPD.     

Systematic review of anaemia and inflammatory markers in chronic obstructive pulmonary disease

This systematic review synthesizes the relevant published articles on the prevalence of anaemia in patients with chronic obstructive pulmonary disease (COPD) and its relationship with inflammatory markers. The upregulation of erythropoietin in anaemia maintains homeostasis. However, anaemic COPD patients do not respond to increased levels of erythropoietin. The increased levels could be an indicator of the peripheral erythropoietin resistance in COPD. Anaemia and inflammation are associated with an increased risk of hospitalization and mortality in these patients. The understanding of anaemia in chronic inflammation is that anaemia is at least partially due to the excessive production of inflammatory cytokines, which can contribute to improvements in the management, prognosis, and survival of patients with COPD and anaemia.     

Usage of inhalation devices in asthma and chronic obstructive pulmonary disease: a Delphi consensus statement

Objectives: The study aimed to assess usage of inhalation devices in asthma and chronic obstructive pulmonary disease (COPD).

Methods: In this two-round Delphi survey, 50 experts in asthma and COPD completed a 13-item, Internet-based, self-administered questionnaire about choice of inhalation device, training and monitoring of inhalation techniques, the interchangeability and the role of costs in the selection of inhalation devices. For each item, the median (central tendency) and interquartile ranges (degree of consensus) were calculated.

Results: Experts considered that the choice of inhalation device was as important as that of active substance (very good consensus) and should be driven by ease of use (good to very good consensus) and teaching (very good consensus). Experts recommended giving oral and visual instructions (good consensus) and systematic monitoring inhalation techniques. Pulmonologists and paramedics have predominantly educational roles (very good consensus). Experts discouraged inhalation device interchangeability (good consensus) and switching for cost reasons (good to very good consensus) without medical consultation (good consensus).

Conclusions: The results of this survey thus suggested that inhalation devices are as important as active substances and training and monitoring are essential in ensuring effective treatment of asthma and COPD. Inhalation device switching without medical consultation should be avoided.     

高血糖对慢性阻塞性肺疾病患者预后的影响

目的住院期间血糖升高对慢性阻塞性疾病急性发作期(COPD-AE)患者近期预后的影响。方法对131例COPD-AE患者入院3d内进行空腹血糖测定。根据空腹血糖把患者分为血糖异常组(空腹血糖≥6.1mmol/L),血糖正常组(空腹血糖<6.1mmol/L)。结果82例(62.6%)COPD-AE患者空腹血糖≥6.1mmol/L,其中确诊糖尿病患者36例(27.5%),血糖升高组多为高龄患者,住院期间病死率明显高于血糖正常组(P<0.05)。结论住院期间血糖升高是影响COPD-AE患者预后的一个重要的危险因素,对血糖升高的患者应给予积极的治疗。     

肺内吸入给药治疗哮喘和慢性阻塞性肺病研究进展

哮喘和慢性阻塞性肺疾病(COPD)是最常见的呼吸道疾病之一,全球分别有3 亿和2.1 亿患者。肺部吸入给药是治疗和管理哮喘、COPD 等呼吸道疾病的首选给药方式,而患者的依从性与该类制剂的疗效优劣有密切关系。综述现在已经上市的肺部吸入给药治疗哮喘和慢性阻塞性肺疾病的主要剂型和药品,以及雾化吸入剂、定量吸入剂和干粉吸入剂对患者依从性的影响,并认为提高患者依从性需要反复提供给患者个性化用药和正确使用给药装置的指导。     

脉冲振荡法结合舒张试验在支气管哮喘与慢性阻塞性肺疾病鉴别诊断中的应用

目的探讨脉冲振荡法（IOS）结合舒张试验在支气管哮喘与慢性阻塞性肺疾病（COPD）鉴别诊断中的意义及临床应用价值。方法对78例支气管哮喘急性发作期及88例慢性阻塞性肺疾病患者在吸人支气管舒张剂前后分别进行IOS的测定,比较两组支气管舒张试验前后IOS测得值及其变化差异。结果吸人沙丁胺醇前支气管哮喘组与慢性阻塞性肺疾病组IOS值无显著差异（P〉0．05）,但吸人沙丁胺醇后支气管哮喘组5Hz和20Hz振荡频率时粘性阻力（R5、R20）、5Hz振荡频率时电抗（X5）及共振频率（Fres）的变化幅度均明显大于慢性阻塞性肺病组（P〈0．05）,其中以Fres改善最明显。支气管哮喘组与FEV1增加相关性密切的IOS值依次为Fres〉R5〉X5〉R20。结论脉冲振荡法结合支气管舒张实验有助于支气管哮喘与慢性阻塞性肺疾病的鉴别诊断。     

咳喘医药联合门诊服务模式的实践与探索

目的 探索咳喘医药联合门诊服务模式。方法 收集我院2021年6月至12月期间在联合门诊就诊的咳喘疾病（包括慢性阻塞性肺疾病、哮喘）患者,评估患者在药学服务干预前后吸入装置的使用评分、依从性(MMAS-8)评分、临床有效情况、不良反应发生率及患者满意度,并进行统计学分析。结果 与干预前比较,干预后吸入装置使用评分、MMAS-8评分、支气管哮喘控制测试(ACT）/慢性阻塞性肺疾病评估测试（CAT）评分均有提高,差异有统计学意义(P<0.05) ;患者对药学服务的满意度在94.75%以上。结论 我院开设的咳喘医药联合门诊提供的药学服务可以帮助咳喘疾病患者正确使用吸入装置,提高用药依从性,更好地控制病情,减少药物不良反应发生,医药联合门诊规范工作模式的积极尝试和探索具有一定可行性。     

慢性阻塞性肺疾病的肺康复研究进展

慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)常见症状包括慢性咳嗽、咳痰、气短及呼吸困难等,其病死率较高。2017年欧洲呼吸学会和美国胸科协会明确提出COPD患者的肺康复治疗。肺康复治疗作为COPD的非药物治疗方法,可有效改善患者症状及预后。本文主要综述了肺康复的概念、肺康复所包含的具体内容及疗效评估的最新研究,同时分析其存在的不足以及发展前景。     

Investigational p38 inhibitors for the treatment of chronic obstructive pulmonary disease

Introduction: The p38 protein kinases, in particular p38α and p38β, regulate the production of multiple inflammatory mediators. Consequentially, considerable effort has been focused on trying to develop p38 inhibitors for the treatment of inflammatory diseases. Some 20 p38 inhibitors have progressed to clinical development, mostly for the treatment of rheumatoid arthritis, but with little success. Increasingly, interest has turned to their use in other indications and notably chronic obstructive pulmonary disease (COPD).

Areas covered: In this review, the author discusses the eight p38 inhibitors that have been clinically evaluated. Acumapimod is the only one of four orally delivered inhibitors that remains in active development while Phase II results of PH-797804 and losmapimod are compared. The activity of two inhibitors designed for inhaled delivery, RV-568 and PF-03715455, is compared but little is known about AZD-7624 or the discontinued GSK-610677.

Expert opinion: Results from animal models provide a clear rationale for developing p38 inhibitors for COPD, and appear to be (partially) validated by the efficacy seen with PH-797804 and losmapimod. Inhaled delivery provides the opportunity to enhance p38 inhibition in the lung while reducing unwanted systemic effects of p38 inhibition. Validation of this hypothesis should come from the results of the recently completed Phase II study with RV-568.     

Doxofylline: a promising methylxanthine derivative for the treatment of asthma and chronic obstructive pulmonary disease

Background: Doxofylline, a methylxanthine derivative, has recently drawn attention because of its better safety profile and similar efficacy over the most widely prescribed analogue, theophylline, indicated for asthma and chronic obstructive pulmonary disease. Objective: This article attempts to discuss the pharmacodynamics/pharmacokinetics and clinical efficacy of doxofylline. Method: An extensive search in three electronic databases (Unbound Medline, Pubmed and Sciencedirect) and internet search engines (Scirus and Google Scholar) were used to identify the clinical studies on doxofylline. The literature search was carried out without time constraints to ensure maximum coverage of existing literature on doxofylline. Results/conclusion: In a relatively large number of comparative studies, doxofylline is indicated to have less affinity for α₁ and α₂ receptors than theophylline. Unlike theophylline, doxofylline does not antagonize calcium channels, nor does it interfere with the influx of calcium into the cells, which probably reduces the cardiac side effects. Moreover, it does not affect sleep rhythm, gastric secretions, heart rate and rhythm and CNS functioning. Numerous reports available regarding the better tolerability of doxofylline than theophylline prove it as a potential bronchodilator with promising pharmacological behavior. However, despite its superior safety and clinical efficacy, the potential of doxofylline has not been fully exploited.     

Decreased expression of human aquaporin-5 correlated with mucus overproduction in airways of chronic obstructive pulmonary disease

AIM: To investigate the relationship between aquaporin-5 (AQP5) expression and mucus overproduction in the airways of Chinese patients with chronic obstructive pulmonary disease (COPD) and the correlation with pulmonary function change. METHODS: Bronchial tissues were obtained from fiberoptic bronchoscopy and bronchial biopsy in West China Hospital from April to July 2004. Twenty-five patients were diagnosed as COPD patients, and another 20 were diagnosed as the control patients. The expressions of AQP5, mucin 5AC (MUC5AC), and mucin in bronchial tissues were detected by semiquantitative RT-PCR, in situ hybridization, and immunohistochemical and alcian blue-periodic acid-Schiff (AB-PAS) staining, respectively. RESULTS: Compared with the control group, an attenuated expression of AQP5 was detected throughout the bronchial tissues from patients with COPD (P<0.01), but no difference existed in the lung tissues (P>0.05). Simultaneously, increased staining of MUC5AC and mucus in submucosal glands were noted (P<0.01, respectively). Smoking attenuated the expressions of AQP5 and increased the staining of MUC5AC and mucus in submucosal glands in the COPD groups (P<0.01), while there were no significant differences observed in the control group (P>0.05). The decreased expression of AQP5 mRNA was correlated with forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) (r=0.60, P<0.01), FEV1% predicted value (r=0.60, P<0.01), maximal expiratory flow in 50% vital capacity (V50) % predicted value (r=0.55, P<0.01), and maximal expiratory flow in 25% vital capacity (V25) % predicted value (r=0.45, P<0.01). The decreased expression was negatively correlated with MUC5AC mRNA of the epithelium airways (r=-0.45, P<0.01) and the AB-PAS-stained area of submucosal glands (r=-0.61, P<0.01). The upregulation of MUC5AC mRNA correlated with the positively AB-PAS-stained area of submucosal glands and correlated negatively with FEV1/FVC (r=-0.53; P<0.01), FEV1% predicted value (r=-0.53; P<0.01), V50% predicted value (r=-0.48; P<0.01), and V25% predicted value (r=-0.43; P<0.01). CONCLUSION: The attenuated gene expression of AQP5 existed in the airways of Chinese COPD patients, which was complicated by mucus hypersecretion. The decreased expression of AQP5 mRNA may be related to the severity of airflow obstruction.     

中药治疗慢性阻塞性肺疾病的作用机制研究进展

慢性阻塞性肺疾病（COPD）是一种气流不完全受限的常见慢性呼吸系统疾病,发病率高、致死率高,已成为全球范围内威胁人类健康的主要慢性病之一,目前尚无有效的治疗药物,近年来COPD的防治已成为广大医药工作者的研究热点,尤其是中药对于COPD作用机制的研究较多。中药能够控制气道和肺部炎症、改善气道重塑、降低气道反应、调控氧化–抗氧化过程,并对蛋白酶–抗蛋白酶失衡、免疫失衡及肺功能、血液流变学、血清标记物的病理改变起到一定的调整作用。归纳总结中药治疗COPD作用机制的研究,为中药COPD作用机制的研究及COPD的治疗提供新的思路和途径。     

葆乐辉对慢性阻塞性肺疾病患者肺功能的疗效观察

目的　了解无水茶碱控释片 (葆乐辉 )对慢性阻塞性肺疾病 (COPD)的肺功能疗效。方法　采用随机公开分组对照法 ,前瞻性比较口服葆乐辉与不服用葆乐辉对慢性阻塞性肺疾病患者肺功能的疗效。将患者分为治疗组 ( 3 1例 )及对照组 ( 3 1例 )。治疗组采用葆乐辉 40 0mg d进行 2个月的连续口服治疗。对照组 3 1例不服该药。服药前及服药后第 2个月末 ,分别测定肺功能。结果　治疗组肺功能的主要指标FVC、FEV1 及FEV1 FVC %较服药前及对照组明显改善 ,差异有显著性。结论　使用无水茶碱控释片 (葆乐辉 )治疗慢性阻塞性肺疾病 ,对其肺功能改善有肯定疗效。说明即使对可逆性不大的气流阻塞的COPD患者 ,葆乐辉也有肯定疗效 ,且葆乐辉为控释制剂 ,患者的依从性明显优于普通氨茶碱     

Pharmacoeconomics of the management of acute exacerbations of chronic obstructive pulmonary disease

Acute exacerbations of chronic obstructive pulmonary disease (COPD) impose a significant burden on society in terms of morbidity, mortality, reduced quality of life and healthcare expenditure. New generations of antibiotics are used to treat exacerbations, and other modes of delivery involving home support are being implemented. The optimal strategy to manage exacerbations on pharmacoeconomic grounds depends on issues such as diagnosis of an exacerbation and safety, effectiveness and costs of available alternatives. This review outlines the state of the art of pharmacoeconomic knowledge of the management of acute COPD exacerbations. It presents estimates of the level and distribution of costs associated with exacerbations and reports on the cost-effectiveness or cost-utility of antimicrobial therapy and other approaches to the management of exacerbations.     

Dipyridamole treatment in chronic obstructive airways disease: Effect on platelet regeneration time

Summary The platelet regeneration time (PRT) determined in a group of hypoxaemic patients with chronic obstructive airways disease (COAD), before and after treatment with dipyridamole 150 mg tid, was compared with a group of control subjects. The PRT was computed by a modified non-radioisotope technique and was expressed as t_1/2 in days. The patient group showed a significantly shortened PRT as compared to controls of the same age and sex (2.10±0.16 vs 3.65±0.26 days;p<0.001). One month of dipyridamole administration resulted in prolongation of the PRT in COAD patients (2.10±0.16 days pre-treatment vs 2.75±0.20 post-treatment;p<0.01), without affecting the platelet cyclo-oxygenase system. This study indicates that dipyridamole may be beneficial in pathological conditions, which are characterized by increased platelet turnover, possibly leading to frequent thromboembolic complications.     

The economic impact of chronic obstructive pulmonary disease

The cost burden associated with chronic bronchitis and emphysema, collectively known as chronic obstructive pulmonary disease (COPD), is large. The disease impacts not only on patients but caregivers and society as well. An estimated 16 million people in the US are currently diagnosed with COPD, the majority having chronic bronchitis. Mortality associated with this disease is on the upswing, as is its prevalence in the female population and the elderly. It is currently the fourth most common cause of death both in the US and worldwide. To date, the only proven cost-effective therapies for the disease are the cessation or prevention of smoking, which is the single most common cause of COPD, and vaccination to prevent influenza and pneumococcal infection. Hospitalisation and associated costs represent the greatest healthcare expenditures for people with the disease. Long-term oxygen therapy is also among the most costly interventions in terms of total money spent on direct medical costs for COPD treatment, although it is probably cost-effective because of its positive impact on rates of mortality. In fact, oxygen therapy is the only intervention to date that has been shown to decrease death rates due to COPD. Appropriate treatment with medication has the potential to decrease resource utilisation but does not appear to affect death rates. Similarly, pulmonary rehabilitation programs appear to benefit patients in terms of quality of life; however, long-term cost-effectiveness and effects on mortality have yet to be elucidated. Indirect costs also contribute a substantial part of the economic burden of the disease but are significantly harder to quantify.     

Treatment of Chlamydia pneumoniae infection and chronic obstructive pulmonary disease

Chronic obstructive lung disease (COPD) is a general term for chronic, irreversible lung disease that combines qualities of emphysema and chronic bronchitis. The standard definition of chronic bronchitis is a productive cough for three months per year (for at least two consecutive years) without an underlying aetiology. Acute exacerbation of chronic bronchitis (AECB) represents a common complaint that leads patients to seek medical attention. COPD and AECB are directly responsible for the overuse of antibiotics in the developed world. Fifty per cent of exacerbations have either viral or non-infectious origin. For this reason, antibiotic use remains controversial. Among other bacteria, Chlamydia pneumoniae is responsible for 4 – 16% of AECB in hospitalised or out-patients, although among smokers and people using steroids, the incidence is 34%. C. pneumoniae may either be the sole causative agent or a co-agent in AECB. This paper reviews the management of COPD/AECB with respect to antibiotic use. Diagnosis and antimicrobial therapy relevant to Chlamydia in the management of AECB are also evaluated in this review.