Relative bioavailability of salbutamol to the lung following inhalation when administration is prolonged

AIMS: Urinary salbutamol post-inhalation has been shown to be an index of lung deposition. The possibility of using the urinary method for prolonged periods of inhalation (such as nebulized therapy) has been evaluated. METHODS: On separate study days volunteers received salbutamol 5 x 100 microg via either oral administration (ORAL), oral with 5 g oral charcoal (ORAL + C), inhaled from a metered dose inhaler (MDI) or MDI plus 5 g oral charcoal (MDI + C). Each dose was separated by 2 min, i.e. administration time of 8 min. Urine samples were provided at 0, 30, 40, 60 and 120 min postdose. Also seven subjects inhaled 5x100 microg doses from the MDI on five separate occasions and provided urine 0-30 min post dose. RESULTS: No salbutamol was detected in urine samples following ORAL + C. The mean (s.d.) amounts of salbutamol excreted in the urine in the first 30 min post ORAL, MDI and MDI + C were 0.42 (0.55), 11.01 (3.77) and 11.60 (3.68) microg, respectively. The ratio of urinary salbutamol following MDI and MDI + C to ORAL in the 0-30 min collection period was 26.2 and 27.8, and between 30 and 40 min postdose was 5.1 and 4.7, respectively. There was no difference between urinary salbutamol over the first 30 min following MDI and MDI + C with a mean ratio (90% confidence interval) of 95.6 (84.0, 107.2). The mean (s.d.) coefficient of variation for the 30 min urinary salbutamol elimination following inhalation of 5 x 100 microg doses from the MDI by seven subjects (on 5 separate study days) was 9.4 (2.3)%. CONCLUSIONS: The 30 min urinary salbutamol method can be used for an inhalation period of up to 8 min to identify the relative bioavailability to the lung. Samples taken after this time period are affected by excretion of the oral absorbed fraction. Most nebulisers deliver their dose within this administration time.     

Effect of plastic spacer handling on salbutamol lung deposition in asthmatic children

AIMS: To study the effects of electrostatics in a plastic spacer on the lung deposition of salbutamol in asthmatic children. METHODS: Twenty-five children (5-12 years) with mild asthma were given salbutamol hydrofluoroalkane pressurized metered dose inhaler 400 micro g via a 750 ml plastic spacer on separate days. Blood samples were taken for plasma salbutamol at 5, 10, 15 and 20 min after inhalation to measure lung bioavailability as a surrogate for relative lung dose. With immediate inhalation following actuation, a new rinsed spacer (NewRinsed ) was compared with a used spacer after repeated daily use (Used ), a spacer rinsed after repeated use (UsedRinsed ) and a spacer primed with benzalkonium chloride to avoid electrostatics (Primed1). In addition, spacers were evaluated using a 15 s inhalation delay following actuation with primed (PrimedDelay) and rinsed (RinsedDelay) spacers. Data were log transformed and expressed as geometric mean fold difference for the average plasma salbutamol concentration (Cav) over 20 min. RESULTS: There were significant differences (P < 0.05) in Cav (as geometric mean fold difference and 95% CI) between Primed1 vs NewRinsed 1.92 fold (95% CI 1.15, 3.20) and between Used vs NewRinsed 1.75 fold (1.11, 2.76). There were no significant differences comparing Primed1, Used or UsedRinsed. There were also significant differences (P < 0.05) between Primed1 vs PrimedDelay 2.34 fold (1.31, 4.19), or vs RinsedDelay 3.59 fold (2.15, 5.99); and for Used vs PrimedDelay 2.14 fold (1.24, 3.69), or vs RinsedDelay 3.28 fold (2.13, 5.04). CONCLUSIONS: The relative lung dose of salbutamol from a plastic spacer may differ considerably depending on spacer handling suggesting that nonelectrostatic spacers may be the best way forward.     

布地奈德联合沙丁胺醇雾化吸入在支气管哮喘急性发作中的临床疗效评价

目的探讨布地奈德联合沙丁胺醇雾化吸入治疗支气管哮喘急性发作的临床效果。方法将本院收治的152例支气管急性发作患者分为对照组和观察组,每组各76例,对照组予以支气管哮喘急性发作常规治疗措施,观察组在对照组治疗的基础上,予以1mg布地奈德（普米克令舒）＋1mg沙丁胺醇雾化吸入治疗,对两组治疗效果进行比较。结果两组患者予以积极有效的救治措施之后,无死亡患者。观察组患者在3d内的治疗缓解效果显著优于对照组（χ2=21.44,P〈0.05）。两组患者治疗后,未发生痰液黏滞、心率失常及呼吸抑制等不良反应。结论布地奈德联合沙丁胺醇雾化吸入治疗支气管哮喘急性发作,可显著缓解患者症状,使肺功能增强,且无明显不良反应,值得推广。     

Relative bioavailability of sodium cromoglycate to the lung following inhalation, using urinary excretion

AIMS: To determine if a urinary excretion method, previously described for salbutamol, could also indicate the relative bioavailability of sodium cromoglycate to the lung following inhalation from a metered dose inhaler. Method Inhaled (INH), inhaled+oral charcoal (INHC), oral (ORAL) and oral+oral charcoal (ORALC) 20 mg doses of sodium cromoglycate were given via a randomised cross-over design to 11 healthy volunteers trained on how to use a metered dose inhaler. Urine samples were collected at 0.0, 0.5, 1.0 and up to 24 h post dosing and the sodium cromoglycate urinary concentration was measured using a high performance liquid chromatographic method. RESULTS: No sodium cromoglycate was detected in the urine up to 24 h following ORALC dosing. A mean (s.d.) of 3.6 (4.3) microg, 10.4 (10.9) microg and 83.7 (71.1) microg of the ORAL dose was excreted, in the urine, during the 0.5, 1.0 and 24 h post dose collection periods, respectively. Following INH dosing, the renal excretion was significantly higher (P<0.01) with 32.9 (14.5) microg, 61.2 (28.3) microg and 305.6 (82.3) microg excreted, respectively. The SCG excreted at 0.5, 1.0 and 24 h collection periods following INHC dosing were 26.3 (8.4) microg, 49.3 (18.1) microg and 184.9 (98.4) microg, respectively. There was no significant difference between the excretion rate of sodium cromoglycate following INHC when compared with INH dosing in the first 0.5 and 1.0 h. CONCLUSIONS: The urinary excretion of sodium cromoglycate in the first 0.5 h post inhalation can be used to compare the relative lung deposition of two inhaled products or of the same product using different inhalation techniques. This represents the relative bioavailability of sodium cromoglycate to the lung following inhalation. Similar 24 h urinary excretion of sodium cromoglycate can be use to compare the total dose delivered to the body from two different inhalation products/inhalation methods. This represents the relative bioavailability of sodium cromoglycate to the body following inhalation. Because of the lack of difference between the INH and INHC in the first 0.5 h, the use of activated charcoal is not necessary when this method is used to compare the relative lung bioavailability of different products or techniques.     

Determination of the bioavailability of gentamicin to the lungs following inhalation from two jet nebulizers

AIMS: To determine the bioavailability of gentamicin to the lung following inhalation from two jet nebulizers. METHODS: Serial urine samples were obtained from 10 volunteers after a 80 mg dose given orally, nebulized from a Pari LC + (PARI) and MicroNeb III (MN) devices, or after a 40 mg intravenous dose. In vitro aerodynamic characteristics of the nebulized doses were also determined. RESULTS: The mean (SD) absolute gentamicin lung bioavailalibility following delivery by PARI and MN devices was 1.4 (0.4) and 1.7 (0.5) %. The mass median aerodynamic diameter (MMAD) of the drug particles from the PARI and MN systems was 8.6 (0.6) and 6.7 (0.5) microm and the corresponding fine particle doses (FPD) were 10.2 (2.8) and 11.7 (1.5) mg. CONCLUSIONS: The MMAD and FPD data reflect the poor lung deposition of gentamicin identified by urinary excretion.     

异丙托溴铵、沙丁胺醇雾化吸入联合甲泼尼龙治疗慢性阻塞性肺病急性加重期的临床观察

目的探讨异丙托溴铵、沙丁胺醇雾化吸人联合静脉注射甲泼尼龙治疗慢性阻塞性肺病（COPD）急性加重期的临床效果。方法将60例COPD急性加重期患者随机分为对照组和治疗组,每组各30例。治疗组雾化吸人0．9％的氯化钠溶液2Hll＋异丙托溴铵500μg、沙丁胺醇2500μg,2次／d,甲泼尼龙40mg静脉注射,1次／d;对照组仅给甲泼尼龙40mg静脉注射,1次／d。比较两组的肺功能、血气分析变化及临床疗效。结果治疗组的总有效率为93．3％,高于对照组的83．3％（P〈0．05）;治疗后,两组的FEV,FEVl／FVC、Pa02较治疗前显著上升,PaCO：较治疗前显著下降,且治疗组的上述各指标改善情况均优于对照组（P〈0．05）。结论异丙托溴铵、沙丁胺醇雾化吸入联合静脉注射甲泼尼龙治疗COPD急性加重期的效果好,可较快改善患者的肺功能及PaO2、PaCO2。     

雾化吸入沙丁胺醇及布地奈德治疗慢性阻塞性肺疾病急性发作

目的 探讨氧启动雾化吸入沙丁胺醇、布地奈德在慢性阻塞性肺疾病急性发作期治疗中的效果。方法 选取慢性阻塞性肺疾病急性发作期患者62例，分为观察组和对照组各31例。观察组在常规综合治疗方法基础上，采用沙丁胺醇雾化液和布地条德混悬液混合雾化吸入治疗。对照组仅采用常规综合治疗方法，观察两组疗效。结果 观察组临床症状改善有效率为93．4％，对照组有效率为67．7％，存在显著差异（P〈0．05）；血气分析用药前后两组间无明显差异，均未见明显不良反应。结论 在慢性阻塞性肺疾病急性加重期患者的治疗中，采用氧启动雾化联合吸入沙丁胺醇、布地奈德效果更好。     

布地奈德联合沙丁胺醇雾化吸入治疗慢性阻塞性肺疾病急性加重期的临床效果观察

目的 观察布地奈德联合沙丁胺醇雾化吸入对慢性阻塞性肺疾病急性加重期（AECOPD）的临床疗效.方法 选择AECOPD患者96例,随机分为观察组48例和对照组48例.对照组在常规治疗基础上加用沙丁胺醇雾化吸入,观察组在常规治疗基础上加用布地奈德联合沙丁胺醇雾化吸入治疗.比较两组患者入院时及治疗7d后呼吸困难评分、动脉血气指标、肺功能指标及不良反应情况.结果 观察组呼吸困难评分低于对照组,动脉血气高于对照组,动脉血二氧化碳分压低于对照组,第1秒用力呼气容积（FEV1）绝对值和FEV1占预计值百分比高于对照组,差异均有统计学意义（P＜0.05）.两组患者治疗期间均无严重不良反应发生.结论 布地奈德联合沙丁胺醇雾化吸入治疗AECOPD效果显著,优于单用沙丁胺醇.     

Relative lung and total systemic bioavailability following inhalation from a metered dose inhaler compared with a metered dose inhaler attached to a large volume plastic spacer and a jet nebuliser

OBJECTIVE: To compare the lung and systemic delivery of salbutamol following inhalation from a metered dose inhaler (MDI), a MDI attached to a spacer (MDI+SP) and a nebuliser (NEB) using a urinary pharmacokinetic method. METHOD: Twelve healthy subjects each provided urine samples at 0, 30 min and pooled up to 24 h after the start of 5 x 100 microg salbutamol inhaled from MDI and MDI + SP and after 2.5 mg was delivered by NEB. Following nebulisation, the amount of salbutamol trapped on an exhalation filter together with that remaining in the apparatus was determined. The amount left in the spacer and that leaving the MDI mouthpiece was also determined. Thus, for all the methods, the amount available for inhalation from each study dose was determined. RESULTS: The mean (+/- SD) 30-min urinary excretion amounts of salbutamol for MDI, MDI+SP and NEB were 12.6+/-3.5, 27.1+/-6.0 and 16.1+/-4.6 microg, respectively. The mean ratios (90% confidence intervals) for MDI+SP compared with MDI and NEB were 230.2 (186.7, 273.8) and 183.0 (146.4, 219.7) (both P values<0.001), respectively, while that between MDI and NEB was 134 (110.4, 159.1) (P < 0.05). The mean (+/-SD) 24-h urinary excretion values for salbutamol and its metabolite were 287.0+/-46.5, 198.1+/-34.7 and 253.4+/-138.3 microg, respectively. Following inhalation a mean of 202.9+/-51.5 microg was left in the spacer. Similarly, after nebulisation 1387.7+/-88.9 microg was left in the nebuliser chamber, 26.3+/-8.0 microg in the mouthpiece and 553.8+/-68.5 microg exhaled. The mean emitted dose from the MDI was 88.4+/-6.1 microg per actuation. When normalised for the amounts available for inhalation, the mean amounts of salbutamol excreted in the urine during the first 30 min were 2.86+/-0.78, 9.15+/-1.69 and 3.06+/-0.70% following MDI, MDI + SP and NEB, respectively. CONCLUSION: Five 100-microg doses inhaled from a metered dose inhaler attached to a spacer delivered more to the lungs and less to the systemic circulation than either the same doses from a metered dose inhaler used alone or five times the dose given via a jet nebuliser. Spacers should be routinely used instead of nebulisers to manage patients unless they are short of breath.     

Relative bioavailability of terbutaline to the lung following inhalation, using urinary excretion

AIMS

The aim of the study was to determine the relative lung and systemic bioavailability of terbutaline.

METHODS

On separate days healthy volunteers received 500 µg terbutaline study doses either inhaled from a metered dose inhaler or swallowed as a solution with and without oral charcoal. Urine samples were provided at timed intervals post dosing.

RESULTS

Mean (SD) urinary terbutaline 0.5 h post inhalation, in 12 volunteers, with (IC) and without (I) oral charcoal and oral (O) dosing was 7.4 (2.2), 6.5 (2.1) and 0.2 (0.2) µg. I and IC were similar and both significantly greater than O (P < 0.001). Urinary 24 h terbutaline post I was similar to IC + O. The method was linear and reproducible, similar to that of the urinary salbutamol method.

CONCLUSIONS

The urinary salbutamol pharmacokinetic method post inhalation applies to terbutaline. Terbutaline study doses can replace routine salbutamol during these studies when patients are studied.     

G5振动排痰仪联合沙丁胺醇雾化吸入对COPD急性加重期临床效果观察

目的：研究G5振动排痰仪联合沙丁胺醇雾化吸入对慢性阻塞性肺疾病急性加重期排痰的临床效果。方法：COPD急性加重期患者120例,均符合中华医学会呼吸学会2007年制定的COPD诊断标准。将患者随机分为3组,A组40例,B组40例,C组40例,入选患者均给予氧疗、抗感染、纠正酸碱失衡和电解质紊乱,A组在此基础上采用G5振动排痰仪（美国通用医学物理治疗设备公司生产的G5振动排痰机）治疗,选择频率为15～30Hz,每次15min,3次/d。B组在此基础上采用沙丁胺醇雾化治疗,将沙丁胺醇雾化液5mg用0.9%NaCl溶液稀释成5ml溶液加入德国PARI（百瑞）雾化吸入器内吸入,雾化时间为20min,3次/d,5d为1个疗程。C组采用沙丁胺醇雾化联合振动排痰仪治疗,雾化后间隔30min应用振动排痰仪治疗,3次/d。结果：C组与A组和B组患者的排痰量比较差异有统计学意义（P〈0.05）。A组和B组患者的排痰量比较差异无统计学意义。结论：沙丁胺醇雾化吸入联合G5振动排痰仪对慢性阻塞性肺疾病急性加重期排痰效果明显,是治疗慢性阻塞性肺疾病急性加重期的优先选择。     

肺癌术后肺纤维化急性加重的诊疗进展

特发性肺纤维化（IPF）是一种特殊类型的间质性肺炎,以缓慢进展为特点,其病变局限在肺部,老年人多见,一部分病例会出现急性加重的过程,表现为原有肺部病变突然恶化和致死性的呼吸衰竭,并出现新的肺部阴影和弥漫性肺泡病理改变。特发性肺纤维化急性加重（AEIPF）可发生于接受肺切除术后的原发性肺癌患者,起病通常呈急性或亚急性过程,病因尚不明确,通常认为与不明原因的肺损伤相关,起病隐匿,病情进展迅速,病死率高,而且在临床缺乏常规的预防和治疗措施,成为困扰临床医生的难题。本文就肺癌术后特发性肺纤维化急性加重的病因、发生的危险因素、预测指标、预防、治疗、预后等方面做一系统综述。     

Impacts after inhalation of nano- and fine-sized titanium dioxide particles: morphological changes,translocation within the rat lung,and evaluation of particle deposition using the relative deposition index

A 3-week inhalation study with nano- and fine-sized titanium dioxide (TiO₂) with 3, 28, and 90 days recovery time was performed in female Wistar rats. Lung volume measurements, histology, electron microscopy, hematology, and bronchoalveolar lavage (BAL) fluid analyses were conducted and the relative deposition index (RDI) was calculated. Minimal inflammatory changes in the lungs, leucopenia, and a decrease in β-glucuronidase were observed. Particles were mainly deposited in alveolar macrophages and, to a lesser extent, in type-I pneumocytes, and this was quantified using the RDI. Rarely, particle-laden cells were observed inside capillaries. Therefore, minimal translocation of particles into the bloodstream has to be considered. Significant changes, e.g. in elicited effects or translocation behavior, between nano- and fine-particle-treated groups were not observed.     

Relative bioavailability of salbutamol to the lung following inhalation via a novel dry powder inhaler and a standard metered dose inhaler

Aims The number of dry powder inhaler (DPI) devices could increase because they are easier to use than a metered dose inhaler (MDI). Using urinary excretion, the relative bioavailability of salbutamol to the lungs and the body for a prototype DPI has been compared with an MDI.
Methods A randomized, double-blind, two way crossover study compared the amount of salbutamol in the urine 30  min following inhalation of 2×100  μg salbutamol from a prototype DPI (Innovata Biomed Ltd, UK) and a Ventolin^® (Allen and Hanburys Ltd, UK) MDI in 10 volunteers. The amount of salbutamol and its metabolite, the ester sulphate conjugate, renally excreted up to 24  h post inhalation was also determined to evaluate the relative bioavailability of salbutamol to the body.
Results The mean (s.d.) 30  min post-treatment urinary excretion for the prototype DPI and MDI was 8.4 (2.6) and 5.0 (1.9)  μg, respectively ( P <0.001). The total amount of salbutamol and its ester metabolite excreted in the urine over the 24  h period after inhalation was 187.9 (77.6) and 137.6 (40.0)  μg ( P <0.05).
Conclusions The prototype DPI delivered more salbutamol to the body and the lungs than a conventional MDI. This finding supports further development of the prototype DPI. The urinary salbutamol method is able to discriminate between two different inhalation systems.     

益肺胶囊联合布地奈德雾化治疗慢性阻塞性肺疾病急性加重期的临床研究

目的探讨益肺胶囊联合布地奈德气雾剂雾化吸入治疗慢性阻塞性肺疾病急性加重期临床疗效。方法选取2016年3月—2017年2月太仓市中医医院收治的慢性阻塞性肺疾病急性加重期患者92例为研究对象,按照随机数字表法将所有患者分为对照组和治疗组,每组各46例。对照组雾化吸入布地奈德气雾剂,1 000μg/次,1次/d。治疗组在对照组基础上口服益肺胶囊,1.2 g/次,3次/d。两组患者均连续治疗2个月。观察两组的临床疗效,比较两组的免疫功能和肺功能。结果治疗后,对照组和治疗组的总有效率分别为73.91%、91.30%,两组比较差异有统计学意义(P0.05)。治疗后,治疗组自然杀伤(NK)细胞、CD~(3+)、CD~(4+)、CD~(4+)/CD~(8+)水平均明显升高,同组治疗前后比较差异具有统计学意义(P0.05);且治疗组这些观察指标明显高于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,两组一秒用力呼气容积(FEV1)、FEV1/用力肺活量(FVC)、最大呼气流速(PEF)、第1秒用力呼气容积占预计值百分比(FEV1%pred)均明显升高,同组治疗前后比较差异具有统计学意义(P0.05);且治疗组这些观察指标明显高于对照组,两组比较差异具有统计学意义(P0.05)。结论益肺胶囊联合布地奈德气雾剂雾化治疗慢性阻塞性肺疾病急性加重期具有较好的临床疗效,能改善肺功能,调节免疫功能,具有一定的临床推广应用价值。     

雾化吸人和口服糖皮质激素治疗慢性阻塞性肺疾病急性加重期的效果分析

目的探讨雾化吸入和口服糖皮质激素治疗慢性阻塞性肺疾病急性加重期（AECOPD）的效果。方法将重庆市第五人民医院2009年4月至2011年4月收治的83例慢性阻塞性肺疾病急性加重期患者随机分为雾化组（雾化吸入布地奈德混悬液治疗）和口服组（口服泼尼松治疗）;回顾分析患者的临床资料：①两组治疗前、治疗后3 d、7 d和14 d的肺功能指标（FEV1、FEV1/FVC、FEV1占预计值比例和PEF）、血气分析（血PaO2、PaCO2和pH）及症状得分情况,并计算治疗后各时间点相对于治疗前各指标的改善情况;②治疗过程中的不良反应。结果两组治疗后7 d和14 d的肺功能指标、血气分析和症状得分均优于治疗前;雾化组治疗后3 d的以上指标优于治疗前和口服组,治疗后3 d的改善值大于口服组,其余时间点与口服组无差异;雾化组的不良反应发生率低于口服组（P〈0.01）。结论雾化吸入治疗可快速缓解慢性阻塞性肺疾病急性加重期症状,但后期治疗效果与口服组相当,且不良反应少,可推广使用。     

23价肺炎球菌多糖疫苗和流行性感冒疫苗防治老年慢性肺病急性发作的研究

目的:评价老年慢性肺病人群联合接种23价肺炎球菌多糖疫苗和流行性感冒疫苗,预防慢性肺病急性发作的效果。方法:选取2008年10月到2009年3月的稳定期老年慢性肺病患者192例。随机分为接种23价肺炎球菌多糖疫苗和流行性感冒疫苗的试验组97例和接种流行性感冒疫苗的对照组95例。在基线调查的基础上,接种后1年内随访两组慢性肺病第一次急性发作时间情况。结果:试验组急性发作的发生率53.6%(52/97)低于对照组72.6%(69/95)(χ2=6.659,P=0.010)。接种23价肺炎球菌多糖疫苗和流行性感冒疫苗能减少慢性肺病急性发作的发生率,其保护效率为26.2%。两组病死率相近,分别为8.2%(8/97)和11.6%(11/95)(χ2=0.597,P=0.440)。Kaplan-Meier生存函数发现试验组慢性肺病急性发作未发生率低于对照组(log-rank检验,χ2=8.065,P=0.005)。结论:联合接种23价肺炎球菌多糖疫苗和流行性感冒疫苗能减少慢性肺病急性发作的发生,具有一定的保护效力。