哮喘病人支气管舒张反应曲线的研究

目的探讨哮喘病人支气管舒张反应曲线的特点。方法应用福莫特罗进行支气管舒张试验，多时间点观测34例哮喘病人和14例健康人肺通气功能随时问的变化。结果哮喘病人。各项指标在15min、30min、60min、120min、240min的测量值较基础值增高，差异均有统计学意义（P〈0．05），在相同时间点哮喘患者各项肺通气功能指标的测量值较正常对照下降，差异有统计学意义（P〈0．05）。哮喘患者支气管舒张反应曲线有逐渐上升的变化趋势，正常对照支气管舒张反应曲线成波浪型变化。哮喘病人各项肺通气功能指标中，FEV1、FEV1／FVC、PEF、FEF25、FEF25/75，随时间点变化的拟合二次曲线模型方程有统计学意义（P〈0．05）；正常对照组的拟合二次曲线模型方程，无统计学意义（P〉0．05）。结论哮喘病人支气管舒张反应曲线有一定的特点，并且气道扩张存在一定的规律。     

Triple Therapy in COPD: What We Know and What We Don't

Triple inhaled therapy for chronic obstructive pulmonary disease (COPD) consists of an inhaled corticosteroid (ICS), a long-acting β₂-agonist (LABA) and a long-acting muscarinic antagonist (LAMA) taken in combination. Triple therapy is recommended by the Global initiative for Chronic Obstructive Lung Disease (GOLD) for patients who experience recurrent exacerbations despite treatment with either a dual bronchodilator (preferred initial therapy) or LABA/ICS combination (alternative initial therapy). Although there is evidence for the greater efficacy of triple therapy compared with LABA/ICS and LAMA monotherapy with regards to improved lung function, health status, and exacerbation rate, the efficacy of triple therapy when compared with dual bronchodilation (LABA/LAMA) is as yet unknown. As ICS use is associated with an increased risk of developing pneumonia, it is important to assess the risk/benefit ratio of triple therapy on an individual basis, and identify patients most likely to benefit. The role of elevated blood eosinophils as a biomarker for the identification of candidates for ICS treatment is currently debated, and further prospective evidence is required. This review assesses evidence for the efficacy and safety of triple therapy and postulates on the prospective evidence from ongoing studies. The potential for treating patients who experience further exacerbations on dual bronchodilation according to phenotype is also considered, as well as withdrawal of ICS from triple therapy in patients who are unlikely to benefit.     

Use of olprinone, a phosphodiesterase III inhibitor, in an asthmatic patient

Phosphodiesterase (PDE) III exists in airway smooth muscles. In addition, PDEIII inhibitors have been suggested to relax airway smooth muscle by increasing intracellular cAMP concentrations. We report a successful use of olprinone, a PDEIII inhibitor, for treatment of an asthmatic attack. A 15-year-old male patient treated with oral theophylline 400 mg x d(-1) was anesthetized with propofol, fentanyl and ketamine for knee joint surgery. Immediately after tracheal intubation, an asthma attack occurred with peak airway pressure (Paw)>40 cmH2O. Thus, propofol 20 mg was additionally given to increase anesthetic depth, and Paw gradually decreased to 30 cmH2O. In addition, we started monitoring bronchial cross-sectional area using a superfine fiberoptic bronchoscopic method previously reported. However, as Paw did not further decrease for 30 min, olprinone was intravenously infused (10 microg x kg(-1) x 10 min(-1) + 0.3 microg x kg(-1) x min(-1), total 5 mg). Olprinone infusion rapidly decreased peak Paw from 30 cmH2O to 24 cmH2O and increased bronchial cross-sectional area by 50%. These findings suggest that olprinone produced bronchodilation.     

Muscular and cardiorespiratory effects of pseudoephedrine in human athletes

AIMS: Pseudoephedrine (PSE) is a readily available over-the-counter nasal decongestant which is structurally similar to amphetamine and is included on the International Olympic Committee's list of banned substances. However to date, little research has supported its putative ergogenic effect. This study investigated whether a 180 mg dose of PSE ingested 45 min prior to exercise enhanced short-term maximal exercise performance and/or altered related physiological variables. METHODS: A randomised, double-blind, crossover study in 22 healthy male athletes. RESULTS: Maximum torque (mean +/- s.d., n = 22) produced in an isometric knee extension exercise was 321.1+/-62.0 Nm (PSE) and 295.7+/-72.4 Nm (placebo), and peak power obtained on the 'all-out' 30 s cycle test was 1262.5+/-48.5 W (PSE) and 1228.4+/-47.1 W (placebo) (P<0.01, P<0.03, respectively). Subjects were estimated to be producing 96.9+/-2.4% of their maximal possible isometric leg extension force after PSE ingestion, but only 95.3+/-2.4% when PSE was not ingested. Bench press tasks and total work during the cycle test were not affected by the ingestion of PSE. Lung function was altered following ingestion of PSE (P<0.05) with FEV1 and FVC significantly increased (P<0.02, P<0.01, respectively) although the FEV1/FVC ratio was not altered. Heart rate was significantly elevated by the ingestion of PSE immediately following the 30 s cycle sprint (P<0.01) however, lactate concentration was not altered by the ingestion of PSE. CONCLUSIONS: The administration of a 180 mg dose of PSE increased maximum torque, produced in an isometric knee extension and produced an improvement in peak power during maximal cycle performance, as well as improving lung function.     

Large Porous Particles for Sustained Protection from Carbachol-Induced Bronchoconstriction in Guinea Pigs

Purpose. To determine whether a new formulated albuterol aerosol could sustain inhibition to bronchoconstriction for approximately one day in guinea pigs challenged with carbachol. Methods. Large and porous particles, comprising a combination of endogenous or PDA-approved excipients and albuterol sulfate, were prepared by spray drying using a NIRO portable spray drier. The anesthetized animals inhaled 5 mg of large porous or small nonporous particles by forced ventilation via cannulae inserted in the lumen of their exposed tracheae. At regular intervals over a period of 36 hours after drug delivery, airway resistance was determined in response to carbachol challenge dose. Results. Whereas inhalation of small nonporous albuterol particles protected from the carbachol-induced bronchoconstriction for up to 5 hours, inhalation of large porous albuterol particles produced a significant inhibition of carbachol-induced bronchoconstriction for at least 16 hours. Conclusions. The absence of substantial side effects, verified over a period of 24 hours by evaluating cardio-respiratory parameters as well as pulmonary inflammation, supports the utility of large porous albuterol particles for sustained therapies in asthma and other types of lung disease.Dr. Ben-Jebria is also affiliated with     

Anti‐bronchoconstrictor activities and side effect potential of inhaled formoterol and (S,R)‐epiformoterol in the rhesus monkey

In a recent patent, the (S,R) isomer of epiformoterol was claimed to be a bronchodilator with reduced adverse effects compared to racemic formoterol. We initiated the present study to seek direct evidence for the claim. Anaesthetised, spontaneously breathing rhesus monkeys were set up for measuring airways resistance. Blood pressure and heart rate were measured concomitantly to gauge systemic exposure and the potential for side effects. Formoterol, 1.2µg/kg, administered by aerosol, induced rapidly developing, sustained inhibition of the bronchoconstrictor responses to aerosolised methacholine accompanied by tachycardia. (S,R)‐epiformoterol, 63µg/kg, induced anti‐bronconstrictor effects and an associated tachycardia, which were superimposable with those induced by racemic formoterol at 1.2µg/kg. Thus, (S,R)‐epiformoterol is a long‐acting anti‐bronchoconstrictor agent in the rhesus monkey and causes an associated tachycardia. This profile is not qualitatively different from that of racemic formoterol but does differ from that of salmeterol, which, in this model, shows lower efficacy and more pronounced tachycardia for an equivalent degree of anti‐bronchoconstrictor activity. Thus, the claim that (S,R)‐epiformoterol shows bronchodilator activity with reduced adverse effect potential compared to racemic formoterol is not supported by the present data. Drug Dev. Res. 57:1–5, 2002. © 2002 Wiley‐Liss, Inc.     

Capnovolumetry: a new tool for lung function testing in children with asthma

In capnovolumetry, the expiratory CO2 concentration of exhaled air is plotted against the volume and thereby allows to determine functional dead space volumes. This method might offer additional information in lung function testing in children and adolescents with bronchial asthma. We aimed at determining whether a bronchospasmolysis (BSL) effect in the lower airways could also be detected by capnovolumetry as reflected by changes in the functional threshold dead space volumes (VDT). In 47 patients (aged 4-16 years) with a mild persistent bronchial asthma, VDT were determined before and after bronchodilation prior to starting therapy with inhaled steroids and after 6 months of treatment. Additionally, spirometry and body plethysmography were performed in all patients. There were significantly higher VDT values after BSL before and after 6 months of therapy (P<0.0001). VDT values before BSL were tendatively higher after 6 months of therapy compared with baseline values (P=0.07). VDT values correlated with parameters derived from conventional pulmonary function testing, i.e. vital capacity, forced expiratory volume in 1 s (FEV1), and maximum expiratory flow (MEF50). As VDT values particularly reflect the volumes of the lower bronchi this method may provide supplementary information to conventional lung function tests which are based on breathing mechanics. This seems to be especially helpful in situations where body plethysmography is not available or cooperation in forced expiration manoeuvres is insufficient.     

Can Patients With Asthma Feel Inhaler Therapy Working Right Away? Two Clinical Trials Testing the Effect of Timing of Assessment on Patient Perception

Background. Feeling a maintenance therapy work right away may provide positive reinforcement and may offer one way to improve adherence in patients with asthma. Precise measurement is required to accurately compare the presence of this effect across clinical trial treatment groups. Methods. Two randomized, controlled studies tested whether timing of assessment (daily vs weekly, study 1; and predose vs postdose, study 2) influenced patients' reports of whether they can feel a medication working right away (perception), and their satisfaction with this perception (satisfaction). These 2-week US-based multicenter double-blind, parallel-group studies included patients ≥18 years of age with mild to moderate persistent asthma. In each, patients were randomized to one of two drugs with different onset profiles: budesonide/formoterol pressurized metered-dose inhaler (pMDI) 80/4.5 μg × 2 inhalations (160/9 μg) twice daily or budesonide pMDI 80 μg × 2 inhalations (160 μg) twice daily. Patients were further randomized to complete previously validated perception and satisfaction questions in a cross-over fashion, either daily and weekly (N = 123) or predose and postdose (N = 134). Patient surveys also assessed perceptions of the onset of effect of medication and their value of these perceptions. Results. No significant differences were observed in patients' reports of perception, either daily versus weekly or predose versus postdose. A statistically significant difference in satisfaction was found in study 1 only, favoring weekly recall (p < 0.05), with sensitivity analysis showing no difference by treatment group (p = 0.162). Across both studies, most patients (87%) who perceived their inhaler working right away (136 of 157 patients) identified positive airway sensations. Most patients reported that feeling their medication work right away is reassuring and would help them manage their asthma. Conclusion. Assessment timing has no effect on patient response to the perception of feeling a medication working right away. Differences found in satisfaction levels reported with weekly versus daily recall were consistent across treatment groups, indicating that no bias was introduced in favor of either treatment group. Patients characterized the perception of feeling a maintenance therapy working right away as easier breathing and reported this perception as beneficial to patient self-care.     

Nilotinib: a novel Bcr-Abl tyrosine kinase inhibitor for the treatment of leukemias

COPD is a syndrome characterised by progressive airflow limitation caused by chronic inflammation of the airways and lung parenchyma. It is the most common lung disease, carrying a significant mortality, morbidity and healthcare costs worldwide. COPD is associated with increased activity of parasympathetic nervous system that plays a dominant role in the regulation of airways tone. As cholinergic tone seems to be the only reversible component of COPD, muscarinic receptor antagonists (MRAs) represent the most effective class of bronchodilators in COPD. Thus MRAs remain the mainstay of pharmacotherapy in COPD as they increase expiratory flow rate by decreasing airway smooth muscle tone and mucus secretion leading to enhanced lung function. The discovery of the different muscarinic receptor subtypes that are involved in the regulation of airway function led to the development of more subtype-selective MRAs for the treatment of COPD. Furthermore, it has been hypothesised that the compounds preferentially antagonise the muscarinic M3 receptor-mediated effects would provide better clinical efficacy with a reduction in adverse events related to the blockade of other muscarinic receptor subtypes. Based on this hypothesis, the present multi-centre, randomised, placebo-controlled study assessed the effectiveness of selective muscarinic receptor (M3) antagonist through oral delivery in COPD patients.     

Pulmonary Deposition and Clinical Response of99mTc-Labelled Salbutamol Delivered from a Novel Multiple Dose Powder Inhaler

Pulmonary deposition of ^99mTc-labelled sulbutamol was determined after delivery from a novel multiple dose powder inhaler (Easyhaler^®). The clinical efficacy of the inhalation powder, evaluated simultaneously with gamma camera detection, was compared with that obtained after drug delivery from a metered dose inhaler-spacer combination. The study was performed as an open, non-randomized cross-over trial. A single dose of radiolabelled inhalation powder was inhaled on the first and the inhalation aerosol, as control, on the second study day. Sulbutamol sulphate was labelled with ^99mtechnetium, and the inhalation powder was formulated by mixing radioactive drug particles with carrier material. Aerodynamic properties of the radiolabelled inhalation powder were similar to those of the unlabelled salbutamol powder. Delivered dose from the breath-actuated powder inhaler was adjusted to be equal to two puffs from a conventional aerosol actuator with a short plastic mouthpiece. Twelve non-smoking asthmatic patients participated in the trial. The mean pulmonary deposition of 24% was obtained after drug delivery from Easyhaler^® powder inhaler. Clinical efficacy of the medications was similar in terms of area under the FEV₁ curve, maximum FEV₁ and the improvement ratio. Thus it can be suggested that powder delivery from Easyhaler^® powder inhaler and the aerosol delivery through the spacer are equally effective.