Inhaled salmeterol/fluticasone propionate: a review of its use in chronic obstructive pulmonary disease

The salmeterol/fluticasone propionate dry powder inhaler (DPI) [Advair Diskus, Seretide Accuhaler] contains the long-acting beta2-adrenoceptor agonist salmeterol and the inhaled corticosteroid fluticasone propionate. In the US, twice-daily salmeterol/fluticasone propionate 50/250 microg is approved for use in adults with chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis, and in the EU, the twice-daily 50/500 microg dosage is approved for use in patients with severe COPD, repeat exacerbations and significant symptoms despite bronchodilator therapy. In patients with moderate-to-severe COPD, twice-daily inhaled salmeterol/fluticasone propionate 50/250 or 50/500 microg for 24-52 weeks improves predose forced expiratory volume in 1 second (FEV1) significantly more than salmeterol monotherapy, improves postdose or postbronchodilator FEV1 significantly more than fluticasone propionate monotherapy and results in clinically significant improvements in health-related quality of life. Salmeterol/fluticasone propionate 50/500 microg significantly reduced annual COPD exacerbations, especially in severe COPD. Some corticosteroid-related adverse events were increased in recipients of fluticasone propionate with or without salmeterol versus salmeterol monotherapy or placebo; withdrawal from fluticasone propionate, including combination therapy, needs careful management to minimise COPD exacerbations. The DPI combining a corticosteroid and long-acting beta2-agonist provides benefits over monotherapy and may encourage patient compliance in COPD.     

Development of an economic model to assess the cost effectiveness of treatment interventions for chronic obstructive pulmonary disease

OBJECTIVE: To develop a Markov model that allows the cost effectiveness of interventions in patients with chronic obstructive pulmonary disease (COPD) to be estimated, and to apply the model to investigate the cost effectiveness of an inhaled corticosteroid/long-acting beta(2)-adrenoceptor agonist (beta(2)-agonist) combination (salmeterol/fluticasone propionate) versus usual care. METHODS: A Markov model consisting of four mutually exclusive disease states was constructed (mild, moderate and severe disease, and death). The transition probabilities of disease progression (for smokers and ex-smokers) and death were derived from the published medical literature. The model outputs were costs, exacerbations, survival, QALYs and cost effectiveness. The model was made fully probabilistic to reflect the joint uncertainty in the model parameters. Efficacy data for the combination of inhaled salmeterol/fluticasone propionate 50/500microg twice daily in poorly reversible COPD patients with a history of exacerbations were obtained from the 1-year TRISTAN (TRial of Inhaled STeroids ANd long-acting beta-agonists) study and applied to the model, based on patient profiles representative of COPD clinical trials. RESULTS: According to the model, the mean life expectancy with usual care alone (placebo group) was 8.95 years, which decreased to 4.08 QALYs once adjusted for quality and discounted, at a lifetime discounted cost of Can 16,415 dollars per patient (year 2002 values). Assuming that salmeterol/fluticasone propionate reduced exacerbation frequency only (base case analysis), the estimated mean survival time remained unchanged but there was an increase in the number of QALYs (4.21) for an estimated lifetime cost of Can 25,780 dollars, resulting in a cost-effectiveness ratio of Can 74,887 dollars per QALY (95% CI 21,985, 128,671) versus usual care. If a survival benefit was assumed for salmeterol/fluticasone propionate, the incremental cost per QALY was Can11,125 dollars (95% CI 8710, dominated) versus usual care. If the combination achieved around a 10% improvement in forced expiratory volume in 1 second, leading to delayed progression to more severe disease states, the benefits translated into an incremental cost per QALY of Can 49,928 dollars (95% CI 37 269, 66,006) versus usual care. CONCLUSIONS: This Markov model allows, for the first time, a means of estimating the long-term cost effectiveness and cost utility of interventions for COPD. Initial evidence suggests that for patients with poorly reversible COPD and a documented history of frequent COPD exacerbations, the addition of salmeterol (a long-acting beta(2)-agonist) to fluticasone propionate (an inhaled corticosteroid) is potentially cost effective from the Canadian healthcare payer's perspective. However, the precision of this estimate will be improved when additional data are available from clinical trials such as the ongoing TORCH (TOwards a Revolution in COPD Health) study.     

Salmeterol/fluticasone propionate: a review of its use in the treatment of chronic obstructive pulmonary disease

Salmeterol/fluticasone propionate (Seretide, Advair, Viani) administered using a multidose dry powder inhaler (Diskus, Accuhaler) is approved for use in the treatment of chronic obstructive pulmonary disease (COPD) in numerous countries.Salmeterol/fluticasone propionate administered twice daily via dry powder inhaler is effective and generally well tolerated in patients with COPD. Although not associated with a statistically significant reduction in mortality versus placebo in the TORCH study (p = 0.052), salmeterol/fluticasone propionate reduced the rate of decline in lung function over the 3 years of the trial and was associated with lower exacerbation rates than the component monotherapies or placebo; other trials revealed clinically significant improvements in health status and dyspnoea scores with salmeterol/fluticasone propionate. Results of the INSPIRE trial suggest that salmeterol/fluticasone propionate is associated with a significantly lower mortality rate than tiotropium bromide monotherapy in patients with COPD; the two treatments had similar effects in terms of exacerbation rates and lung function. Thus, salmeterol/fluticasone propionate is an important option in the treatment of patients with COPD who are appropriate candidates for combination therapy with a long-acting bronchodilator and an inhaled corticosteroid.     

IL-8 production by macrophages is synergistically enhanced when cigarette smoke is combined with TNF-α

Macrophages are key inflammatory cells in chronic obstructive pulmonary disease (COPD). The pathophysiology of cigarette smoke-induced lung emphysema is complex but there is a clear role for reactive oxygen species (ROS, such as peroxynitrite), tumor necrosis factor (TNF-α) and interleukin (IL)-8. We investigated whether TNF-α or cigarette smoke medium (CSM) alone or in combination induces the production of IL-8 by human macrophages or monocyte lymphoma U937. CSM and TNF-α induce a dose- and time-dependent increase in IL-8 production. Interestingly, when sub-threshold concentrations of CSM and TNF-α were co-incubated, a 1500% increase in IL-8 production was observed compared to either of the compounds alone. Similar results were obtained with TNF-α and the peroxynitrite donor SIN-1. Moreover, the overproduction of IL-8 was associated with an enhanced increase in the translocation of NF-κB and an enhanced decrease in glutathione levels. Preincubation of the cells with antioxidants, such as N-acetyl-l-cysteine (NAC), prevented the overproduction of IL-8 and activation of NF-κB.In conclusion, CSM exposure of macrophages up-regulates the expression and the production of IL-8 via reactive oxygen species and NF-κB activation. Moreover, CSM dramatically enhances the production of IL-8 in combination with TNF-α. Based upon the strong synergistic action, a combination therapy directed against ROS and TNF-α could be a new approach to stop the progression in lung damage during emphysema.     

Desensitisation of mast cell beta2-adrenoceptor-mediated responses by salmeterol and formoterol

1. The long-acting beta(2)-adrenoceptor agonist formoterol (10(-10)-10(-6) m) inhibited the IgE-dependent release of histamine from human lung mast cells in a concentration-dependent manner. Formoterol was more potent and a full agonist relative to the nonselective beta-adrenoceptor agonist isoprenaline. By contrast, the long-acting beta(2)-adrenoceptor agonist salmeterol (10(-10)-10(-6) m) was about two-thirds less efficacious than either formoterol or isoprenaline as an inhibitor of histamine release. 2. Isoprenaline, formoterol and salmeterol (all at 10(-5) m) increased total cell cAMP levels in mast cells over basal by 361+/-90 (P<0.05), 321+/-89 (P<0.05) and 64+/-24% (P>0.05), respectively. 3. Long-term (24 h) incubation of mast cells with formoterol (10(-6) m) or salmeterol (10(-6) m) essentially abolished the subsequent ability of isoprenaline to inhibit histamine release. Both formoterol and salmeterol were more effective at inducing the functional desensitisation than isoprenaline (10(-6) m) or the short-acting beta(2)-adrenoceptor agonist salbutamol (10(-6) m). 4. The desensitisation induced by long-term treatments with salmeterol and formoterol was specific for beta(2)-adrenoceptor-mediated inhibition of histamine release as the inhibitory effects of alternative cAMP-elevating compounds, prostaglandin E(2), a receptor-mediated activator of adenylate cyclase, and forskolin, a direct activator of adenylate cyclase, were unaffected by desensitising treatments. 5. Radioligand binding studies were performed to determine beta(2)-adrenoceptor density in cell membranes after pretreatment (24 h) of cells with agonists. Isoprenaline, formoterol and salmeterol (all at 10(-6) m) reduced beta(2)-adrenoceptor density by 13+/-5 (P>0.05), 49+/-13 (P<0.05) and 35+/-17% (P>0.05), respectively. 6. These data indicate that long-term exposure of mast cells to both salmeterol and formoterol can cause substantial levels of desensitisation to beta(2)-adrenoceptor-mediated responses in mast cells.     

Inhaled salmeterol/fluticasone propionate: a review of its use in asthma

Salmeterol/fluticasone propionate, administered twice daily via a multidose dry powder inhaler (Seretide/Advair Diskus), Seretide Accuhaler or metered-dose hydrofluoroalkane (chlorofluorocarbon-free) inhaler (Seretide Evohaler), is a combination of the long-acting beta(2)-adrenoceptor agonist (beta(2)-agonist) [LABA] salmeterol and the corticosteroid fluticasone propionate.Maintenance therapy with combined salmeterol/fluticasone propionate is at least as effective in improving lung function and symptoms and is as well tolerated in patients with asthma as concurrent salmeterol plus fluticasone propionate. In patients previously receiving as-required short-acting beta(2)-agonists (SABAs) or inhaled corticosteroids, salmeterol/fluticasone propionate was significantly more effective in providing asthma control than fluticasone propionate and in improving lung function and asthma symptoms than inhaled corticosteroids (at equivalent or higher dosages), salmeterol or montelukast (as monotherapy or in combination with fluticasone propionate). Salmeterol/fluticasone propionate was more effective in improving asthma symptoms than adjusted-dose budesonide/formoterol in patients with uncontrolled asthma despite treatment with inhaled corticosteroids with or without a LABA in a well designed 1-year study. In pharmacoeconomic analyses, salmeterol/fluticasone propionate compared favourably with inhaled corticosteroids and mono- or combination therapy with oral montelukast. Salmeterol/fluticasone propionate is, therefore, an effective, well tolerated and cost-effective option for the maintenance treatment of patients with asthma.     

Inhaled salmeterol/fluticasone propionate combination: a pharmacoeconomic review of its use in the management of asthma

Asthma guidelines recommend an inhaled corticosteroid plus a long-acting inhaled beta(2)-agonist (beta(2)-adrenoceptor agonist) as the preferred maintenance therapy for moderate and severe persistent asthma. Advair/Seretide Diskus also registered as Accuhaler is fixed-dose salmeterol (a long-acting inhaled beta(2)-agonist) and fluticasone propionate (a corticosteroid) administered via a single powder inhalation device. The clinical effectiveness of salmeterol/fluticasone propionate in patients with persistent asthma symptoms has been established in comparative clinical trials. Pharmacoeconomic analyses, based on data from these clinical trials, have been conducted from a healthcare payer perspective in various countries. In patients with asthma not controlled with inhaled corticosteroids, salmeterol/fluticasone propionate was associated with more favourable (lower) cost-effectiveness ratios than fluticasone propionate monotherapy, oral montelukast plus inhaled fluticasone propionate, inhaled budesonide, and inhaled formoterol plus budesonide. As the initial maintenance therapy in patients with persistent asthma symptoms while receiving short-acting beta(2)-agonists alone, salmeterol/fluticasone propionate was cost effective relative to montelukast monotherapy. Although the total cost of asthma management tended to be slightly higher with salmeterol/fluticasone propionate than with fluticasone propionate or montelukast monotherapy, salmeterol/fluticasone propionate consistently had a more favourable cost-effectiveness ratio in terms of per successfully treated week or symptom-free day and/or was associated with small incremental costs to achieve significant additional clinical benefits. In clinical practice, salmeterol plus fluticasone propionate was associated with lower asthma-related costs than treatment with other maintenance therapies.In patients with asthma symptoms despite treatment with inhaled corticosteroids, salmeterol/fluticasone propionate produced clinically meaningful improvements in overall Asthma Quality of Life Questionnaire (AQLQ) scores relative to salmeterol or placebo monotherapy, in emotional function domain scores relative to fluticasone propionate or budesonide, and in asthma symptoms domain scores relative to budesonide. In patients with persistent asthma symptoms while receiving short-acting beta(2)-agonists alone, salmeterol/fluticasone propionate produced clinically meaningful improvements in overall AQLQ scores compared with fluticasone propionate or montelukast. CONCLUSIONS: Pharmacoeconomic analyses indicate that salmeterol/fluticasone propionate administered via a single inhaler represents a cost-effective treatment option (relative to fluticasone propionate at the same nominal dosage, budesonide, formoterol plus budesonide and montelukast plus fluticasone propionate) in patients with asthma not controlled with inhaled corticosteroid therapy. In patients with asthma not controlled with short-acting beta(2)-agonists alone, salmeterol/fluticasone propionate is a cost effective treatment relative to monotherapy with montelukast. Importantly, salmeterol/fluticasone propionate is also associated with improvements in health-related quality of life.     

The role of MAPK and Nrf2 pathways in ketanserin-elicited attenuation of cigarette smoke-induced IL-8 production in human bronchial epithelial cells

Cigarette smoking is a major risk factor in chronic obstructive pulmonary disease (COPD) with chronic airway inflammation as a key feature. Blockade of serotonin receptor 2A (5-HTR(2A)) with ketanserin has been found to improve lung function in COPD patients. Furthermore, ketanserin has been shown to possess anti-inflammatory properties in vivo. In this study, we investigated the antioxidative and anti-inflammatory properties of ketanserin and its underlying mechanism of action on cigarette smoke-induced interleukin (IL)-8 release in vitro. Primary normal human bronchial epithelial cells and human bronchial epithelial cell line (BEAS-2B) were treated with or without ketanserin prior to exposure to cigarette smoke medium (CSM). Exposure to CSM caused elevation of both mRNA and release of IL-8 with increased phosphorylation of p38 and extracellular signal-regulated kinases 1 and 2 (ERK1/2). Consistently, CSM-induced IL-8 release was blocked by SB203580, U0126, or MEK1 small interfering RNA (siRNA) but not SP600125. On the other hand, CSM caused a dose-dependent decrease in the ratio of reduced glutathione to oxidized glutathione (rGSH/GSSG) together with an increased translocation of Nrf2 to the nucleus demonstrated by Western blot analysis. Knock down of Nrf2 by siRNA completely blocked CSM-induced IL-8 release. Ketanserin suppressed CSM-induced IL-8 release by inhibiting p38, ERK1/2 MAPK, and Nrf2 signaling pathways and partially inhibited CSM-induced reduction of rGSH/GSSG ratio. Our data demonstrated the novel antioxidative and anti-inflammatory role of ketanserin via the Nrf2 signaling pathway in CSM-exposed human bronchial epithelial cells. This may open up new perspectives in the development of novel therapeutic targets in the treatment of cigarette smoke-related COPD.     

沙美特罗/氟替卡松对慢性阻塞性肺疾病患者急性加重期气道炎症的影响

目的 探讨沙美特罗/氟替卡松对慢性阻塞性肺疾病（COPD）患者气道炎症的影响.方法 选择40例COPD急性加重期患者,随机分成沙美特罗/氟替卡松治疗组（A组）和对照组（B组）,并选择18例健康人作为健康对照组（C组）.观察其支气管肺泡灌洗液（BALF）中自细胞介素8（IL-8）和肿瘤坏死因子α（TNF-α）的变化.结果 A组和B组患者BAL中[IL-8（10.60±1.42）μg/L,（10.77±1.98）μg/L]及TNF-α含量[（14.80±2.05）μg/L,（14.70±2.03）μg/L]均高于C组[（3.40±0.65）μg/L,（4.67±1.01）μg/L]（均P〈0.01） 治疗前BALF中IL-8与TNF-α含量,A组[（10.60±1.42）μg/L,（14.80±2.05）μg/L]和B组[（10.77±1.98）μg/L,（14.70±2.03）μg/L]差异均无统计学意义（均P〉0.05）,但治疗两周后,A组BALF中IL-8及TNF-α含量[（4.39±0.92）μg/L,（5.84±1.26）μg/L]较B组[（9.69±1.43）μg/L,（12.88±2.51）μg/L]均明显下降（均P〈0.01）.结论 沙美特罗/氟替卡松可以有效控制COPD患者的气道炎症.     

Cigarette smoke activates human monocytes by an oxidant-AP-1 signaling pathway: implications for steroid resistance

Smoking cigarettes is a major risk factor for the development of cardiovascular and respiratory disease. Moreover, smoking-induced pathophysiology is often resistant to the anti-inflammatory effects of glucocorticoids. The nature of cigarette smoke-induced inflammation is still not defined, although neutrophil recruitment and activation seem to be consistent features. In the current study, we have used a range of approaches to demonstrate that cigarette smoke activates human monocytes and macrophages to release the CXC chemokine CXCL8 [(interleukin-8 (IL-8)]. Furthermore, we show for the first time that cigarette smoke synergizes with proinflammatory cytokines IL-1beta and tumor necrosis factor-alpha, and it is this interaction that confers steroid resistance to smoke-induced CXCL8 release. We go on to show that smoke-induced activation of human cells is an oxidant-mediated phenomenon acting through activator protein-1, but not nuclear factor kappaB, pathway. These observations add significantly to our understanding of smoke as an inflammatory stimulus that has implications for potential the development of treatments of smoking or related disease.     

茶碱缓释片联合沙美特罗/氟替卡松治疗稳定期重度COPD的疗效观察

目的观察茶碱缓释片联合沙美特罗/氟替卡松治疗稳定期重度慢性阻塞性肺疾病（COPD）的临床疗效。方法将我院2011年7月至2012年7月收治的78例重度COPD稳定期患者随机分为对照组与观察组,分别采取沙美特罗/氟替卡和茶碱缓释片联合沙美特罗/氟替卡松治疗,比较两组临床治疗效果。结果观察组临床总有效率明显高于对照组;两组治疗后FEV1及FVC均明显高于对照组,且观察组增加更为明显（P〈0.05）。结论茶碱缓释片联合沙美特罗/氟替卡松治疗稳定期重度COPD疗效显著,可明显改善患者肺功能和临床症状,值得推广和应用。     

茚达特罗/格隆溴铵治疗慢性阻塞性肺疾病的 成本-效果分析

目的 评估茚达特罗/格隆溴铵与沙美特罗/氟替卡松治疗中度至极重度慢性阻塞性肺疾病(COPD)的成本-效果,为临床用药决策提供依据.方法 利用Markov模型队列模拟分析法预估两种药物治疗COPD的远期效果和费用.结果 茚达特罗/格隆溴铵和沙美特罗/氟替卡松治疗每例COPD患者的平均费用分别为86393.01元和8153...     

沙美特罗/氟替卡松联合噻托溴铵治疗中重度慢性阻塞性肺疾病的临床疗效研究

目的：研究沙美特罗/氟替卡松联合噻托溴铵治疗中重度慢性阻塞性肺疾病（COPD）的临床疗效。方法：68例中重度COPD患者随机分为对照组和治疗组,各34例,对照组给予沙美特罗/氟替卡松,治疗组在给予沙美特罗/氟替卡松的同时吸入噻托溴铵。比较两组治疗前后肺功能指标、呼吸困难评分和6min步行距离（6MWD）。结果：治疗12周后,治疗组肺功能指标（FEV1、FEV1/预计值、FVC和FEV1/FVC）显著改善,与对照组相比,差异均具有统计学意义（P＜0.05）。此外,治疗组治疗12周后呼吸困难评分显著下降,6MWD显著提高,与对照组相比,差异均具有统计学意义（P＜0.05）。结论：沙美特罗/氟替卡松联合噻托溴铵治疗中重度COPD临床疗效显著,优于单独使用沙美特罗/氟替卡松。     

Inhibitors of ceramide de novo biosynthesis rescue damages induced by cigarette smoke in airways epithelia

Exposure to cigarette smoke represents the most important risk factor for the development of chronic obstructive pulmonary disease (COPD). COPD is characterized by chronic inflammation of the airways, imbalance of proteolytic activity resulting in the destruction of lung parenchyma, alveolar hypoxia, oxidative stress, and apoptosis. Sphingolipids are structural membrane components whose metabolism is altered during stress. Known as apoptosis and inflammation inducer, the sphingolipid ceramide was found to accumulate in COPD airways and its plasma concentration increased as well. The present study investigates the role of sphingolipids in the cigarette smoke-induced damage of human airway epithelial cells. Lung epithelial cells were pre-treated with sphingolipid synthesis inhibitors (myriocin or XM462) and then exposed to a mixture of nicotine, acrolein, formaldehyde, and acetaldehyde, the major toxic cigarette smoke components. The inflammatory and proteolytic responses were investigated by analysis of the mRNA expression (RT-PCR) of cytokines IL-1β and IL-8, and matrix metalloproteinase-9 and of the protein expression (ELISA) of IL-8. Ceramide intracellular amounts were measured by LC-MS technique. Ferric-reducing antioxidant power test and superoxide anion radical scavenging activity assay were used to assess the antioxidant power of the inhibitors of ceramide synthesis. We here show that ceramide synthesis is enhanced under treatment with a cigarette smoke mixture correlating with increased expression of inflammatory cytokines and matrix metalloproteinase 9. The use of inhibitors of ceramide synthesis protected from smoke induced damages such as inflammation, oxidative stress, and proteolytic imbalance in airways epithelia.

     

Information from US FDA

The U.S. Food and Drug Administration today approved the first generic of Advair Diskus (fluticasone propionate and salmeterol inhalation powder) for the twice-daily treatment of asthma in patients aged four yearsand older and maintenance treatment of airflow obstruction and reducing exacerbations in patients with chronic obstructive pulmonary disease (COPD). Mylan obtained approval to market its generic inhaler in three strengths: fluticasone propionate 100 mcg/ salmeterol 50 mcg, fluticasone propionate 250 mcg/ salmeterol 50 mcg and fluticasone propionate 500 mcg/ salmeterol 50 mcg     

Inhibitory effect of p38 mitogen-activated protein kinase inhibitors on cytokine release from human macrophages

BACKGROUND AND PURPOSE: Macrophages release cytokines that may contribute to pulmonary inflammation in conditions such as chronic obstructive pulmonary disease. Thus, inhibition of macrophage cytokine production may have therapeutic benefit. p38 MAPK may regulate cytokine production, therefore, the effect of two p38 MAPK inhibitors, SB239063 and SD-282, on the release of TNF-alpha, GM-CSF and IL-8 from human macrophages was investigated. EXPERIMENTAL APPROACH: Cytokine release was measured by ELISA. Immunoblots and mRNA expression studies were performed to confirm p38 MAPK isoform expression and activity. Macrophages were isolated from lung tissue of current smokers, ex-smokers and emphysema patients and exposed to lipopolysaccharide. These cells then released cytokines in a concentration-dependent manner. KEY RESULTS: SB239063 only inhibited TNF-alpha release (EC50 0.3 +/- 0.1 microM). Disease status had no effect on the efficacy of SB239063. SD-282 inhibited both TNF-alpha and GM-CSF release from macrophages (EC50 6.1 +/- 1.4 nM and 1.8 +/- 0.6 microM respectively) but had no effect on IL-8 release. In contrast, both inhibitors suppressed cytokine production in monocytes. CONCLUSIONS AND IMPLICATIONS: The differential effects of p38 MAPK inhibitors between macrophages and monocytes could not be explained by differences in p38 MAPK isoform expression or activity. However, the stability of TNF-alpha mRNA was significantly increased in macrophages compared to monocytes. These data suggest a differential involvement for p38 MAPK in macrophage cytokine production compared with monocytes. These effects are not due to lack of p38 activation or p38alpha expression in macrophages but may reflect differential effects on the stability of cytokine mRNA.     

Salmeterol and fluticasone propionate given as a combination

OBJECTIVE: To investigate the potential for systemic pharmacodynamic and pharmacokinetic interactions between inhaled salmeterol and fluticasone propionate when repeat doses of the two drugs are given in combination to healthy subjects. METHODS: Twenty-eight healthy subjects received salmeterol 100 microg, salmeterol 100 microg/fluticasone propionate 500 microg and fluticasone propionate 500 microg via a Diskus dry powder inhaler twice daily for 11 days according to a randomised, double-blind, placebo-controlled, crossover design. Subjects in the placebo group also received a single dose of salmeterol 100 microg on the morning of day 10. On day 10, the systemic effects of salmeterol [on pulse rate, blood pressure, corrected QT (QTc) interval and serum potassium and glucose levels] and fluticasone propionate (on 24-h urinary cortisol and morning plasma cortisol levels) were assessed. Maximal number and affinity of lymphocyte beta2-adrenoceptors and beta2-adrenoceptor polymorphism at loci 16 and 27 were also determined. Plasma pharmacokinetics of salmeterol and fluticasone propionate were determined after the morning dose on day 10. Dosing continued on the evening of day 10 and on day 11, and on day 12 the effect of repeat-dose treatment with salmeterol and salmeterol/fluticasone propionate on the systemic effects of cumulative doses of inhaled salbutamol (up to a total dosage of 3,200 microg) was evaluated. RESULTS: All treatments were safe and well tolerated. With the exception of a higher pulse rate after repeat administration of salmeterol [66.2 beats per minute (bpm) versus 63.6 bpm], there were no significant differences between the single-dose and repeat-dose salmeterol groups. The systemic pharmacodynamic effects of inhaled salmeterol were not affected by the co-administration of fluticasone propionate. Eleven days of treatment with salmeterol induced tachyphylaxis to the systemic effects of cumulative doses of salbutamol; however, co-administration of fluticasone propionate did not affect the response to salbutamol. Fluticasone propionate reduced 24-h urinary cortisol excretion (22.4 microg compared with 48.6 microg with placebo), but this was unaffected by the co-administration of salmeterol. Morning plasma cortisol levels were not reduced compared with placebo. There was no significant treatment effect on lymphocyte beta2-adrenoceptors and no correlation of beta2-adrenoceptor polymorphism at loci 16 and 27 with the development of tachyphylaxis. Salmeterol plasma concentrations were measurable only during the first half-hour after dosing. Co-administration of fluticasone propionate did not affect the peak plasma concentration (Cmax) of salmeterol. For fluticasone propionate, there were no statistically significant differences between salmeterol/fluticasone propionate and fluticasone propionate with respect to Cmax, plasma concentration at the end of the dosing interval (Ct), terminal elimination half-life (t1/2) or time to Cmax (tmax). The area under the concentration-time curve within a dosing interval (AUCt) for fluticasone propionate after inhalation of salmeterol/fluticasone propionate was statistically significantly higher (about 8%) than after inhalation of fluticasone propionate alone (P=0.0135). However, the 90% confidence intervals (CIs) for the AUCt and Cmax ratios for the two treatments were within the accepted limits for bioequivalence (1.03, 1.13 and 0.97, 1.12, respectively). CONCLUSION: These results in healthy subjects indicate that there is no systemic pharmacodynamic or pharmacokinetic interaction between inhaled salmeterol and fluticasone propionate when given in combination.     

重组人粒细胞巨噬细胞集落刺激因子喷雾剂的制备及药效研究

目的研制重组人粒细胞巨噬细胞集落刺激因子喷雾剂,探索其治疗溃疡、烧伤和烫伤的有效性。方法使用合理比例的保护剂、透皮吸收促进剂、抑菌剂和缓冲体系等,将重组人粒细胞巨噬细胞集落刺激因子制备成喷雾剂,通过动物药效实验探索其治疗溃疡、烧伤和烫伤的效果。结果重组人粒细胞巨噬细胞集落刺激因子喷雾剂通过2～8℃条件24个月长期稳定性考察,理化性质和生物活性没有明显变化。通过豚鼠溃疡模型和家兔烧伤和烫伤模型显示,药效非常显著。结论重组人粒细胞巨噬细胞集落刺激因子可制备成喷雾剂,为临床治疗溃疡、烧伤和烫伤等创面疾病提供了依据。     

噻托溴铵联合沙美特罗/福莫特罗对老年稳定期COPD患者肺功能的影响

目的:观察噻托溴铵联合沙美特罗/福莫特罗对老年稳定期慢性阻塞性肺疾病(COPD)患者肺功能的影响。方法:将64例老年稳定期COPD患者按随机数字表法均分为沙美特罗组和福莫特罗组。沙美特罗组患者给予噻托溴铵粉吸入剂,1粒/次(每次应用药粉吸入器吸入1粒),1次/d;沙美特罗-丙酸氟替卡松干粉吸入剂,1吸/次,2次/d。福莫特罗组患者给予噻托溴铵粉吸入剂,用法、用量同沙美特罗组;布地奈德福莫特罗粉吸入剂,1吸/次,2次/d。两组患者疗程均为12周。观察所有患者生活质量、呼吸困难程度和COPD评估测试(CAT),第一秒用力呼气容积(FEV1)、占预计值百分比(FEV1%)、占用力肺活量比值(FEV1/FVC),动脉血氧气分压[pbt(O2)]、动脉血二氧化碳分压[pbt(CO2)],白介素(IL-)6、IL-8、IL-10、肿瘤坏死因子(TNF-)α的变化及不良反应发生情况。结果:治疗后两组患者生活质量三个维度评分、呼吸困难分级和CAT评分、pbt(CO2)、IL-6、IL-8、IL-10、TNF-α水平均显著低于同组治疗前,FEV1、FEV1%、FEV1/FVC、pbt(O2)均显著高于同组治疗前,差异均有统计学意义(P<0.05),各指标组间比较差异无统计学意义(P>0.05)。沙美特罗组不良反应发生率(3.13%)显著低于福莫特罗组(12.5%),两组比较差异有统计学意义(P<0.05)。结论:噻托溴铵联合沙美特罗/福莫特罗均可显著降低患者血浆炎症细胞因子水平,改善患者呼吸功能,提高患者生存质量,但噻托溴铵联合沙美特罗组的安全性更好。