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.     

Successful treatment of eosinophilic otitis media associated with severe bronchial asthma with an anti-IL-5 monoclonal antibody,mepolizumab

Eosinophilic otitis media (EOM), which is characterized by the accumulation of eosinophils in middle ear effusion and the middle ear mucosa, is a refractory type of otitis media that is often associated with asthma. Although an early diagnosis and appropriate treatment are necessary to prevent the progression of hearing loss in patients with EOM, there are currently no well-established treatments for this condition. We treated a 60-year-old male patient with asthma and EOM. The patient’s asthma was poorly controlled, despite the use of high-dose inhaled corticosteroids, long-acting beta-agonist treatment, and the regular use of systemic corticosteroids. Mepolizumab, an anti-IL-5 monoclonal antibody, was started to treat the patient’s refractory asthma. At 4 months after the initiation of mepolizumab treatment, the patient’s asthma, hearing, and middle ear effusion improved. The present case suggests that mepolizumab therapy can control EOM and asthma.     

The role of particle physico-chemical properties in pulmonary drug delivery for tuberculosis therapy

Abstract

There is increasing interest in the use of inhaled aerosol drug therapy for the treatment of tuberculosis (TB). A number of methods of preparation of particles have been employed including spray drying, solvent evaporation, emulsion and phospholipid methods to create microparticles, macroaggregated nanoparticles, solid lipid nanoparticles and liposomes. Each of these methods involves the use of different proportions of additives to aid in the particle formation or to achieve important physico-chemical properties such as ease of dispersion. While these approaches all have merit their practical value is limited by constraints on dose and means of delivery as an aerosol in order to achieve a therapeutic effect. A review of a number of approaches is presented and placed in the context of the need for effective aerosol delivery systems for the treatment of TB as a guide to selection of appropriate excipients, processes and delivery strategies to support product development activities.     

A Comparison of the Individual Best Versus the Predicted Peak Expiratory Flow in Patients with Chronic Asthma

Minority status has been associated with lower asthma medication adherence. We evaluated whether medication beliefs mediated this association. 86 adults with asthma on inhaled corticosteroid therapy completed surveys regarding selected beliefs about asthma medications. Medication adherence for 1 month was electronically measured. Mean daily adherence was lower in minority patients than in Caucasians (p <. 001). Multiple negative asthma medication beliefs were associated with lower adherence (p′s <. 05). Minorities had increased adjusted odds of having a high negative medication beliefs score. Finally, a bootstrapped estimate demonstrated a mediating effect by negative asthma beliefs on the minority status-adherence association (?.073 [95% CI: ?.16, ?.01]).     

两种麻醉方法在老年关节置换中的临床效果比较

目的:探讨全身麻醉和硬腰联合麻醉在老年关节置换患者中的循环系统影响。方法:回顾性分析我院本院2005年～2011年收治的90例老年行关节置换患者,对其应用全麻(GA)和腰-硬膜外联合麻醉(CSEA)的血压及相关情况进行比较。结果:全麻组在麻醉诱导和手术中收缩压和舒张压的变化波动较硬腰组具有明显的统计学意义(P<0.05)。在麻醉诱导后腰硬联合组在改善心肌耗氧量方面明显优于全麻组。结论:硬腰联合麻醉在老年关节置换中具有麻醉平稳、循环系统波动小、操作简单等优势,可作为老年关节置换手术的重要麻醉方式。     

Inhaled ciprofloxacin for chronic airways infections caused by Pseudomonas aeruginosa

Chronic infection of the airways with Pseudomonas aeruginosa represents a therapeutic challenge. Currently existing approaches are particularly based on systemic approaches and this increases the risk of strain resistance selection and is frequently associated with side effects. Therefore, local delivery of antibiotics may reduce these risks and may provide sustained sterilization of the respiratory tract. In fact, this approach was found to be effective with inhaled tobramycin in cystic fibrosis. Inhaled ciprofloxacin (dry powder inhaled formulation or liposomal inhaled formulation) is currently being investigated in chronic infections of the airways in cystic fibrosis, non-cystic fibrosis bronchiectasis and chronic obstructive pulmonary disease, and the initial clinical data are encouraging. This paper presents a perspective on the potential role of inhaled ciprofloxacin in such infections.     

Mometasone furoate dry-powder inhaler for the control of persistent asthma

Mometasone furoate dry-powder inhaler (MF-DPI) is an inhaled corticosteroid (ICS) used for the treatment of persistent asthma in patients aged ≥ 12 years. MF-DPI has low systemic bioavailability and high glucocorticoid receptor affinity compared with most other ICSs and modifies inflammatory mediators involved in the pathogenesis of asthma. MF-DPI, unlike other available ICSs, is approved for initiation as a once-daily in the afternoon (q.d. PM) regimen. Studies show that MF-DPI 200 or 400 μg q.d. PM treatment significantly improves lung function and symptom control in patients with mild, moderate or severe asthma. MF-DPI 400 μg q.d. PM is reported to be equivalent to fluticasone propionate 250 μg b.i.d. and beclometasone dipropionate 168 μg b.i.d. and more efficacious than budesonide 400 μg, b.i.d. or q.d. MF-DPI is generally well tolerated, with minimal effects on the hypothalamic-pituitary-adrenal axis.     

Aerosolized antibiotics: the past,present and future,with a special emphasis on inhaled colistin

Inhaled antibiotics, such as TOBI (a tobramycin solution), gentamicin, colistin and aztreonam lysine (Cayston) have been effectively administered with safety and efficacy in patients with cystic fibrosis and bronchiectasis. In addition, inhaled antibiotics have been administered with safety and efficacy for the prevention and treatment of patients with ventilator-associated tracheobronchitis or pneumonia due to multidrug-resistant Gram-negative bacteria (mainly Pseudomonas aeruginosa or Acinetobacter baumannii). Original studies showed that inhaled colistin resulted in treatment success of nosocomial pneumonia or ventilator-associated pneumonia (VAP) due to multidrug-resistant Gram-negative bacteria. However, although aerosolized colistin seems to be safe and effective for the eradication of P. aeruginosa and the management of pneumonia in cystic fibrosis patients, hospital-acquired pneumonia and VAP due to multidrug-resistant Gram-negative bacteria, it is still unclear if it provides additional benefit in all-cause hospital mortality, or VAP-related mortality rates. For this reason, randomized controlled trials (RCTs) are necessary to validate the efficacy and safety of aerosolized colistin, mainly in patients with nosocomial pneumonia or VAP. In addition, RCTs are necessary to determine the appropriate inhaled colistin dose and the optimal delivery device.     

Budesonide and formoterol combination for the treatment of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality throughout the world. Current guidelines recommend the addition of inhaled steroids to bronchodilators, which are central to the symptomatic management of COPD in patients with severe disease. Budesonide/formoterol is a combination inhaled steroid and long-acting bronchodilator delivered by a dry-powder inhaler, approved for use in COPD. Two large, randomised, double-blind, 12-month studies found that combination budesonide/formoterol is more effective than either component alone in addressing many important aspects of the disease, such as pulmonary function, symptoms, use of relief medication, health-related quality of life and exacerbation in patients suffering from severe COPD. This review discusses the pharmacological and clinical properties of the drug.