Pear shaped spacer nebuhaler compared with nebulised solution for terbutaline administration in acute severe asthma

The efficacy of terbutaline (1 mg) administered from pressurised aerosol through a nebuhaler was compared in a crossover trial with terbutaline (4 mg) as nebulised solution in 20 patients with acute severe asthma. The improvements following the nebuhaler, which did not require an electrical or pressure source, were worthwhile. In contrast to earlier experience in stable asthma, the increases in FEV1 (p = 0.04) and VC (p = 0.05) at 20 minutes were greater following the higher dose as nebuliser solution than following nebuhaler use. Nebuhaler technique requires individual attention since some patients with the severe asthma breathed out through the nebuhaler reservoir due to failure to close the one-way valve.     

Plasma concentrations of disodium cromoglycate after various inhalation methods in healthy subjects

AIMS: To compare the plasma concentrations of disodium cromoglycate (DSCG) following various inhalation procedures in healthy volunteers. METHODS: Nine healthy subjects inhaled 2 mg of aerosol, 20 mg of nebuliser solution only, 20 mg of nebuliser solution mixed with isotonic saline, or 20 mg of nebuliser solution mixed with saline and procaterol, a beta2-adenoceptor agonist, on separate occasions 2-3 weeks apart. Plasma concentrations of DSCG were determined by high-performance liquid chromatography (h.p.l.c.). RESULTS: The peak plasma concentrations of DSCG were 1.5+/-0.7 (range 0.4-2.4) ng ml-1 in the aerosol group, 8.8+/-6.2 (range 5.3-19.9) ng ml-1 in the nebuliser solution only group, 17.2+/-16.3 (range 5.0-38.6) ng ml-1 in the nebuliser solution plus isotonic saline group, and 24.5+/-11. 9 (range 10.2-44.9) ng ml-1 in the nebuliser solution plus saline and procaterol group. Thus subjects who used the nebuliser had markedly higher plasma concentrations of DSCG than subjects who used the aerosol inhaler. CONCLUSIONS: These findings may have important implications for the evaluation of inhalation treatment with DSCG for bronchial asthma.     

Effect of inhaled terbutaline sulphate in relation to its deposition in the lungs

We studied the effects of inhaled terbutaline on FEV₁ and gas exchange, and the pattern of deposition within the lungs. To document this and to estimate the dose of terbutaline administered to the lungs, [^99mTc]DTPA was added to nebulised terbutaline solution. The aerosol was deposited preferentially in large or small airways by using aerosols with different particle mass median diameters (1.5 and 4.8 μm) and different inhalation flow rates (0.25 and 1.01/s). The patients inhaled placebo and then three increasing doses of terbutaline (0.006, 0.02 and 0.08 mg to the lungs). Finally, 2 mg terbutaline was inhaled from a metered dose inhaler via a spacer. After each inhalation FEV₁, PaO₂ and PaCO₂ was measured. The inhalation of small particles at a low flow resulted in a fairly uniform lung deposition, while larger particles at a higher flow resulted in heavy central deposition. Penetration index for small and large particles were 1.3 ± 0.2 and 0.8 ± 0.3 (P < 0.001), respectively. In both groups FEV₁ increased similarly with each dose, and at 0.02 and 0.08 mg the increase was significant (P < 0.01). After eight metered doses of terbutaline sulphate (0.25 mg per dose) inhaled via a spacer, there was a further increase in FEV₁ (P < 0.001). Gas exchange did not differ between the two groups but if they were combined the Da-aO₂ was significantly lower after metered doses than control (P < 0.05). Thus, it appears that the site of deposition is not important for the bronchodilator effect of terbutaline, and gas exchange tended to improve with both modes of administration.     

Identical efficacy of terbutaline multidose dry powder inhaler prior to and after 4 weeks of use by asthmatic patients

We investigated whether the terbutaline multidose dry powder inhaler (Turbuhaler) has the same efficacy after routine daily use as it has when new. Thirty-three adult asthmatic patients were tested on two occasions. The bronchodilatory effect of inhalations of 0.5, 0.5 and 1.0 mg terbutaline at 40-min intervals from the same device was determined prior to and after using the device at least three times a day for 4 weeks. When tested for the second time, 116–186 doses had been inhaled.Although baseline forced expiratory volume in 1 s (FEV₁) was slightly higher after the 4-week treatment period, the bronchodilatory effect of the inhaled terbutaline doses was identical.We conclude that the multidose dry powder inhaler is as effective in delivering terbutaline after a period of routine daily use as it is when new.     

支气管哮喘急性发作期雾化吸入治疗

目的观察雾化吸入布地奈德和特布他林对门诊轻、中急性发作期支气管哮喘患者的疗效。方法48例急性发作期支气管哮喘患者随机分为治疗组（26例）和对照组（22例）。治疗组每天雾化吸入布地奈德和特布他林雾化液7d，7d后吸入布地奈德气雾剂；对照组吸入布地夺德气雾剂和沙丁胺醇气雾剂（分别增加2次的剂量）；均于治疗前和治疗后第3、7和14d给予症状评分。结果治疗组治疗后第3、7d症状评分较对照组明显降低，但第14d两组无明显差异。结论雾化吸入布地奈德和特布他林起效快，可为门诊轻、中度急性发作期哮喘的首选给药方法。     

Inhibition of inhaled metabisulphite-induced bronchoconstriction by inhaled frusemide and ipratropium bromide.

1. The effect of inhaled frusemide and high dose inhaled ipratropium bromide on bronchoconstriction induced by inhaled metabisulphite was studied in 10 atopic volunteers. 2. Frusemide (40 mg), ipratropium bromide (0.5 mg) or saline placebo were administered by nebuliser in a double-blind fashion, prior to construction of a dose-response curve to metabisulphite (2.5-100 mg ml-1). 3. Geometric mean of the provocative dose of metabisulphite that caused a 35% fall in specific airways resistance (sGaw) after placebo was 13 (95% confidence intervals CI 4-36 mumol) compared with 36 (16-78) mumol after ipratropium bromide and 45 (22-94) mumol after frusemide. 4. Mean maximum fall in sGaw was 49 (40-57)% after placebo, 11 (0-22)% after frusemide and -1 (-25-22)% after ipratropium bromide. 5. Frusemide significantly protected against metabisulphite induced bronchoconstriction (P less than 0.005). The protection from high dose ipratropium bromide was also significant (P less than 0.05), but the response was more variable between subjects.     

Effect of formoterol, a long-lasting beta 2-adrenoceptor agonist, against methacholine-induced bronchoconstriction.

1. The effects of a new long-acting inhaled beta 2-adrenoceptor agonist aerosol formoterol (12 micrograms), on FEV1, and on methacholine-induced bronchoconstriction, were compared with those of terbutaline (250 micrograms) and placebo in 12 midly asthmatic subjects. 2. PC20, the concentration of methacholine needed to cause a 20% fall in baseline FEV1, was determined 2 and 5 h after formoterol, terbutaline and placebo on separate days. Baseline PC20 was determined on a different day. 3. Compared with terbutaline and placebo, formoterol hastened recovery from methacholine-induced bronchoconstriction, and significantly increased mean PC20 (by 2.2- and 2.9-fold at 2 and 5 h respectively). 4. Thus, formoterol has a protective effect against methacholine-induced bronchoconstriction which lasts for at least 5 h.     

Protective effect of oral oxyphenonium bromide,terbutaline and theophylline against the bronchial obstructive effects of inhaled histamine,acetylcholine and propranolol

Summary The protective effects of oxyphenonium bromide, terbutaline and theophylline were compared in 8 asthmatic patients by determination of the degree of non-specific airway reactivity after 1 week of oral treatment according to a fixed dose scheme in a double-blind random order: oxyphenonium bromide 3×10 mg; terbutaline 3×5 mg; theophylline 2×300 mg and placebo. Controlled, standardized inhalation provocation tests were carried out with histamine, acetylcholine and propranolol. The study was monitored by measuring blood concentrations of the 3 drugs, and their effect on the plasma cAMP concentration was also determined. Significant protection by oxyphenonium bromide against the bronchial obstructive effects of acetylcholine and propranolol was observed, but not against the effect of inhaled histamine. The other two drugs provided no significant protection against the inhaled agents. The absence of any protective effect of terbutaline and theophylline might have resulted from too low a blood concentration. The observed differences in protection could not be explained by changes in pulmonary function. The study suggests dissociation between the bronchodilating effect of a drug and its protective effect against inhaled substances.     

Enhanced delivery of nebulised salbutamol during non-invasive ventilation

Non-invasive ventilation (NIV) is used to treat acute respiratory failure. Nebulised drugs can be delivered concurrently with NIV or during breaks from ventilatory support. We hypothesised that the amount of nebulised salbutamol inhaled when delivered via bi-level ventilation would be no different to the amount available directly from the same nebuliser. A standard bi-level ventilation circuit was attached to a lung model simulating adult respiration. Drug delivery was compared when salbutamol (5 mg) was nebulised at different positions in the circuit and separately, with no ventilator. The amount of salbutamol contained in various particle size fractions was also determined. Nebuliser position within the NIV circuit was critically important for drug delivery. Optimal delivery of salbutamol occurred with the expiration port between the facemask and nebuliser (647+/-67 micro g). This was significantly better than nebulisation without the ventilator (424+/-61 micro g; P < 0.01). Delivery when the nebuliser was positioned between the facemask and expiration port was 544+/-85 micro g. The amount of salbutamol contained in particles < 5 micro m was significantly increased when the nebuliser was used in conjunction with bi-level ventilation (576+/-60 micro g vs 300+/-43 micro g, P < 0.001). We conclude that nebulised bronchodilator therapy, using a Cirrus jet nebuliser, during bi-level ventilation increases respirable particles likely to be inhaled when the nebuliser is optimally positioned within the circuit.     

Vascular anti-permeability effects of beta-receptor agonists and theophylline in the lung.

In conscious guinea-pigs the effect of theophylline, terbutaline and isoprenaline on histamine-induced increase in lung weight was examined. Animals exposed to a saline aerosol had a lung weight to body weight ratio of about 0.8%. Exposure to a histamine aerosol raised this value to about 1.1 (P less than 0.001). Theophylline 55 mg/kg and 110 mg/kg was given orally, terbutaline 0.1 mg/kg and isoprenaline 0.01 mg/kg and 0.03 mg/kg subcutaneously before exposure to histamine. The three drugs prevented the lung weight effect produced by histamine aerosol (P less than 0.01, P less than 0.001, P less than 0.001, P less than 0.1, P less than 0.001 respectively). Changes in lung blood content did not contribute to the weight-reducing effects. The potency ratio found between terbutaline and isoprenaline suggests that beta-2-receptors might be involved in the anti-permeability effect. Propranolol-treated animals did not survive in the histamine-aerosol unless they received theophylline; neither bronchodilator nor antipermeability effects of theophylline were antagonized by propranolol. It is concluded that in guinea-pigs theophylline and beta-agonists, in bronchodilating doses have the additional effect of preventing permeability oedema in the lung.     

Cardiovascular effects of intramuscular or inhaled terbutaline in asthmatics

8 stable asthmatics were at random given placebo, 0.125 mg, 0.25 mg, 0.5 mg and 1 mg terbutaline intramuscularly or 2.5 mg as inhalation. Systolic time intervals, echocardiographic parameters and peak expiratory flow (PEF) were measured. Maximal circulatory and respiratory response was obtained after 0.5 mg and 0.25 mg, respectively. The circulatory effect of 2.5 mg inhaled terbutaline equalled 0.125 mg given intramuscularly, while this dosage elicited maximal bronchodilator effect. Thus, nebulized terbutaline has only a minimal circulatory effect, and even the intramuscular dosages were without dramatic circulatory side effects.     

The effects of frusemide and triamterene on the hypokalaemic and electrocardiographic responses to inhaled terbutaline.

Fifteen normal volunteers were given 5000 micrograms inhaled terbutaline following three separate 4 day oral treatment periods with placebo, frusemide 40 mg, and frusemide 40 mg plus triamterene 50 mg. Serum potassium (K), and electrocardiographic (ECG) responses were measured after 30 min rest and 30 min after inhalation of terbutaline. Frusemide produced significant hypokalaemia compared with placebo (means and 95% CI): 3.58 mmol l-1 (3.5-3.66) vs 3.88 mmol l-1 (3.8-3.96) (P less than 0.001), and this effect was significantly attenuated by the addition of triamterene: 3.80 mmol l-1 (3.72-3.88) (P less than 0.05). Terbutaline alone also caused significant hypokalaemia: from 3.88 mmol l-1 (3.8-3.96) to 3.35 mmol l-1 (3.24-3.46) (P less than 0.001), and a lower absolute level of K was seen when combined with frusemide: 3.13 mmol l-1 (3.02-3.24) (P less than 0.05). The addition of triamterene conferred no significant protection against the combined hypokalaemia: 3.29 mmol l-1 (3.18-3.4). Changes in T wave amplitude during the study periods showed a similar pattern of response to the hypokalaemic effects. These results show that the hypokalaemic response to terbutaline was additive to that of frusemide, and that triamterene attenuated the hypokalaemic response to frusemide, but not terbutaline.     

Cumulative dose-response study comparing terbutaline pressurized aerosol administered via a pearshaped spacer and terbutaline in a nebulized solution

Summary The bronchodilator effects of cumulative doses of terbutaline 0.125 mg, 0.125 mg and 0.250 mg administered as a pressurized aerosol via a pearshaped spacer were compared with those of terbutaline 1.25 mg, 1.25 mg and 2.50 mg administered as a nebulized solution via a PARI-inhaler Boy. FEV_1.0 and flow-volume curves in 13 patients were measured. Initial placebo treatment of both groups resulted in a significant increase in FEV_1.0, especially when it was given in nebulized form. The increase after active drug was significant after 15 min, with only minor changes during the rest of the trial. The log-dose/increase in FEV_1.0 showed that equipotent doses of pressurized and nebulized terbutaline were in the ratio 1 to 4. Administration by nebulization offered no clear advantage over use of a pressurized aerosol with a pearshaped spacer.     

Effects of terbutaline sulphate aerosol on bronchodilator response and lung mucociliary clearance in patients with mild stable asthma

Ventilatory function and whole lung mucociliary clearance have been assessed in 10 patients with mild stable asthma following inhalation of 1 mg of the beta-adrenergic receptor agonist terbutaline sulphate (Bricanyl, Astra Pharmaceuticals) from a metered dose inhaler (MDI). Compared to placebo inhalation, terbutaline produced marked bronchodilatation (mean percentage increase in FEV1 14%, P less than 0.01). Mucociliary clearance (measured by the in vivo radioaerosol technique) was assessed on three occasions--control, followed by placebo or terbutaline studies in a double-blind, cross-over manner. Particles were removed from the lung at a similar rate in all three studies. The mean (+/- s.e. mean) percentage of aerosol retained in the lungs after 6 h was 58 +/- 5%, 57% +/- 5% and 57 +/- 4% for control, placebo and drug studies respectively. It is concluded that terbutaline sulphate, given as a 1 mg acute dose, does not enhance mucociliary clearance in mild stable asthmatics, although it produces marked bronchodilatation.     

Dose of terbutaline respirator solution in children with asthma.

Twenty children, aged 8 to 17 years, with bronchial asthma were each given 0.02ml/kg, 0.03ml/kg and 0.04ml/kg terbutaline respirator solution (10mg/ml), one dose at a time on three separate occasions. Terbutaline by nebuliser produced a bronchodilator response within five minutes which reached near peak levels by 15 minutes. There was a wide variation in response. A dose of 0.02ml/kg produce a mean increase in FEV1 of 55 percent and an increase in MMEFR of 121 percent. Doses of 0.03ml/kg and 0.04ml/kg given to the same children resulted in slightly better, but not statistically significant different responses. The effect lasted for four hours, although the MMEFR was falling at this time. The baseline FEV1 did not affect the bronchodilator response. An inhalation of 0.02ml/kg of terbutaline respirator solution (10mg/ml) will produce an adequate bronchodilator response in most children.     

特布他林气雾剂治疗支气管哮喘

本文选择100例稳定型慢性支气管哮喘患者,随机分成2组。分别喷用特布他林气雾剂2喷即0.5mg或安慰剂气雾剂。经用药前后肺功能指标(FEV_1)和临床症状比较,结果表明特布他林气雾剂明显优于安慰剂气雾剂(P<0.005)。起效快,平喘作用维持时间达2h左右,副作用少,比较安全。     

Clinical-pharmacokinetic aspects of prolonged effect duration as illustrated by beta2-agonists

Regularity is a key element of maintenance drug treatment; compliance is crucial for treatment success. Once- or twice-daily intake of a drug is always easier to comply with than regimens requiring more frequent dosing. Bronchodilating treatment was used as an example to illustrate how sustained duration of effect can be achieved by two different approaches: oral administration of the terbutaline prodrug bambuterol and inhalation of formoterol. Bioanalytical methods were employed to monitor the kinetic fate of bambuterol and formoterol in plasma, urine, or faeces. Generated terbutaline in plasma was used as a marker of effect for bambuterol. Established clinical laboratory tests were used to assess local and systemic effects of inhaled formoterol compared with salbutamol.Recommended doses of bambuterol, 10-20 mg once daily in adults, normally produced plasma concentrations of the active moiety terbutaline within therapeutically relevant limits. Dose proportionality for terbutaline makes dosing with bambuterol predictable. Compared with adults, children should be given higher doses than indicated by their lower body weight. Pharmacokinetic analysis indicated that absorption of bambuterol was slow and multi-phasic and that slow biotransformation to terbutaline occurred both presystemically and systemically. Systemically circulating formoterol was rapidly eliminated, the inactive (S;S)-formoterol more rapidly than the active (R;R)-formoterol. An inactive phenol glucuronide was the main metabolite, and a previously unknown sulphate metabolite was discovered. Duration of systemically mediated cardiovascular or metabolic side-effects of inhaled formoterol seemed not to differ from those of an inhaled systemically equieffective dose of salbutamol.There was a trend suggesting that the magnitude of systemic side-effects may be less pronounced after inhalation of formoterol compared with a locally equieffective dose of inhaled salbutamol.Both approaches to sustaining stimulation of beta2-adrenoceptors have their pros and cons. Bambuterol can be dosed orally once daily, but full effect is reached slowly.The effect of formoterol is reached within a few minutes, but administration must occur via the lungs, often twice daily. Both treatments, however, give 24-h symptom relief during regular treatment.     

Vascular Anti-permeability Effects of β-receptor Agonists and Theophylline in the Lung

Abstract In conscious guinea-pigs the effect of theophylline, terbutaline and isoprenaline on histamine-induced increase in lung weight was examined. Animals exposed to a saline aerosol had a lung weight to body weight ratio of about 0.8 %. Exposure to a histamine aerosol raised this value to about 1.1(P <0.001). Theophylline 55 mg/kg and 110 mg/kg was given orally, terbutaline 0.1 mg/kg and isoprenaline 0.01 mg/kg and 0.03 mg/kg subcutaneously before exposure to histamine. The three drugs prevented the lung weight effect produced by histamine aerosol (P<0.01, P<0.001, P<0.001, P<0.1, P<0.001 respectively). Changes in lung blood content did not contribute to the weight-reducing effects. The potency ratio found between terbutaline and isoprenaline suggests that β-2-receptors might be involved in the anti-permeability effect. Propranolol-treated animals did not survive in the histamine-aerosol unless they received theophylline; neither bronchodilator nor anti-permeability effects of theophylline were antagonized by propranolol. It is concluded that in guinea-pigs theophylline and β-agonists, in bronchodilating doses have the additional effect of preventing permeability oedema in the lung.     

布地奈德联合特布他林雾化吸入治疗慢性阻塞性肺疾病急性加重期临床疗效

目的探究布地奈德联合特布他林雾化吸入治疗慢性阻塞性肺疾病急性加重期临床疗效。方法将笔者所在医院2009年9月～2011年12月收治的120例慢性阻塞性肺疾病急性加重期患者随机分成实验组60例,给予布地奈德2mL/次联合特布他林2mL/次雾化吸入,2次/d;对照组60例给予甲泼尼龙40mg/d治疗。治疗持续1周,观察两组患者于治疗前后1周的呼吸困难评分、肺功能、动脉血气指标。结果实验组总有效率为91.7%(55/60),优于对照组的75%(45/60),差异有统计学意义(P<0.05);治疗后肺功能改善实验组优于对照组,差异有统计学意义(P<0.05)。结论布地奈德联合特布他林雾化吸入能有效治疗慢性阻塞性肺疾病,及时缓解急性加重期,具有良好的临床疗效。     

Is the cellular uptake of respiratory aerosols delivered from different devices equivalent?

The study focuses on the application of a cell integrated modified Andersen Cascade Impactor (ACI) as an in vitro lung model for the evaluation of aerosols’ behaviour of different formulation devices, containing the same active drug, specifically nebuliser, pressurised metered dose inhaler (pMDI) and dry powder inhaler (DPI). Deposition and transport profiles of the three different inhaled salbutamol sulphate (SS) formulations with clinically relevant doses were evaluated using a modified ACI coupled with the air interface Calu-3 bronchial cell model. Reproducible amounts of SS were deposited on Snapwells for the different formulations, with no significant difference in SS deposition found between the standard ACI plate and modified plate. The transport of SS aerosols produced from pMDI formulation had similar transport kinetics to nebulised SS but significantly higher compared to the DPI, which could have led to the differences in clinical outcomes. Furthermore, drug absorption of different inhaled formulation devices of the same aerodynamic fraction was found not to be equivalent due to their physical chemical properties upon aerosolisation. This study has established an in vitro platform for the evaluation of the different inhaled formulations in physiologically relevant pulmonary conditions.