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Inhaled medications are commonplace for administering bronchodilators, anticholinergics, and corticosteroids. While they have a defined legitimate use, they are also used in sporting events as performance-enhancing drugs. These performance enhancers can be acquired via both legal (i.e., at a pharmacy through over-the-counter medications or through a prescription) and illicit (i.e., black market and foreign pharmacies) means, thus making monitoring procurement impossible. While urine tests can detect these pharmacological agents hours after they have been inhaled, there is a significant lag time before they are observed in urine. Direct detection of these inhaled agents is complicated and requires a multiplexed approach due to the sheer number of inhaled pharmacological agents. Therefore, detection of propellants, which carry the drug into the lungs, provides a simpler path forward toward detection of broad pharmacological agents. In this paper, we demonstrate the first use of terahertz spectroscopy (THz) to detect inhaled medications in human subjects. Notably, we were able to detect and quantitate the propellant, HFA-134a, in breath up to 30 min after using an asthma inhaler, enabling the use of a point-of-care device to monitor exhaled breath for the presence of propellants. We also demonstrate via simulations that the same approach can be leveraged to detect and identify next-generation propellants, specifically HFA-152a. As a result, we provide evidence that a single point-of-care THz sensor can detect when individuals have used pressure-mediated dose inhalers (pMDIs) without further modification of the hardware.

Background and Objectives: The albuterol dropper bottle used to prepare solutions for continuous nebulization contains the preservative benzalkonium chloride (BAC). BAC, by itself, has been shown to cause bronchospasm. We hypothesized that BAC would decrease the therapeutic efficacy of albuterol in patients with acute asthma exacerbations., Methods: We performed a retrospective cohort study comparing the clinical outcomes of patients <18 years of age receiving continuous nebulized albuterol with and without BAC. For the primary end point (duration of continuous albuterol nebulization), we compared the 2 groups with Kaplan-Meier estimate of survival curves, conducted a log-rank test of difference, and adjusted for baseline characteristics using multivariable Cox regression. A P value <.05 was considered significant., Results: A total of 477 patients were included in the analysis (236 exposed to BAC and 241 controls). The duration of continuous nebulization was significantly longer in the BAC group than in the control group (median of 9 vs 6 hours; 15.7% required continuous nebulization compared to 5.8% of controls at 24 hours). The control group was 79% more likely to stop continuous nebulization at any particular point in time (hazard ratio 1.79; 95% confidence interval: 1.45 to 2.22; P < .001) and 43% more likely to stop additional respiratory support (hazard ratio 1.43; 95% confidence interval: 1.16 to 1.75; P < .001)., Conclusions: BAC is a functional albuterol antagonist associated with a longer duration of continuous albuterol nebulization treatment and additional respiratory support, suggesting that preservative-free albuterol formulations are safer for use in continuous nebulization., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Purpose: Asthma is a prevalent lung disorder that cause heavy burdens globally. Inhalation medicaments can relieve symptoms, improve lung function and, thus, the quality of life. However, it is well-documented that patients often do not get the prescribed dose out of an inhaler and the deposition of drug is suboptimal, due to incorrect handling of the device and wrong inhalation technique. This study aims to design and fabricate an acoustic dry powder inhaler (ADPI) for monitoring inhalation flow and related drug administration in order to evaluate whether the patient receives the complete dose out of the inhaler., Methods: The devices were fabricated using 3D printing and the impact of the acoustic element geometry and printing resolution on the acoustic signal was investigated. Commercial Foradil (formoterol fumarate) capsules were used to validate the availability of the ADPI for medication dose tracking. The acoustic signal was analysed with Partial-Least-Squares (PLS) regression., Results: Indicate that specific acoustic signals could be generated at different air flow rates using a passive acoustic element with specific design features. This acoustic signal could be correlated with the PLS model to the air flow rate. A more distinct sound spectra could be acquired at higher printing resolution. The sound spectra from the ADPI with no capsule, a full capsule and an empty capsule are different which could be used for medication tracking., Conclusions: This study shows that it is possible to evaluate the medication quality of inhaled medicaments by monitoring the acoustic signal generated during the inhalation process.

Sustained drug delivery to the respiratory tract is highly desirable for local treatment of chronic lung diseases. In this context, a correlation of in vitro drug release with in vivo efficacy data is essential to accelerate the application of sustained drug delivery system for inhalation into the clinical setting. In this study, budesonide was incorporated into distinct chitosan-based swellable microparticles, which were characterized, and the in vitro drug release behavior determined. The particles were then given to an allergic asthma animal model as single and successive administrations, and the therapeutic response was determined by measuring cell counts, IL-4 and IL-5 levels in bronchoalveolar lavage fluid, IL-4 and IL-5 mRNA in the lung and by histopathologic examination of lung tissues. After a single administration, the time-dependent therapeutic effect of the swellable microparticles was correlated with the in vitro release behavior, which lasted for 12 or 18 h depending on the molecular weight of the chitosan. After seven days of successive treatment, the number of eosinophils decreased further and IL-4 and IL-5 mRNA expression in the lung tissue was more greatly inhibited. Moreover, the chitosan-based swellable microparticles allowed longer administration intervals (every two days), which decreased the required dose for effectiveness by 50%. These results demonstrate that chitosan-based swellable microparticles can sustain the therapeutic effect of budesonide in the respiratory tract which in principal can be applied to other drugs for the treatment of local lung diseases., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Asthma and chronic obstructive pulmonary disease are primarily treated with inhaled medication, but delivery of that medication to its site of action is problematic; patients' ability to use inhalers will affect therapeutic response. Multiple inhaler devices are available but they are variably easy to use with consequent effects on compliance, intentional or otherwise. The Ellipta ® device is a novel blister strip dry powder inhaler with medium resistance and a consistent delivered dose across a range of inspiratory flow rates. The Ellipta has proven easy to use and is preferred by patients across several evaluations and compared with other inhaler devices. The Ellipta is used to administer multiple inhaled medications, all in single daily-dose regimens, making it ideal for patients who struggle with complex inhaled therapy regimens.

The breath-actuated mechanism (BAM) is a mechanical unit included in NEXThaler ® with the role of delaying the emission of the drug until the inhalation flow rate of the patient is sufficiently high to detach the drug particles from their carriers. The main objective of this work was to analyse the effect of the presence of BAM on the size distribution of the emitted drug and its airway deposition efficiency and distribution. Study of the hygroscopic growth of the emitted drug particles and its effect on the deposition was another goal of this study. Size distributions of Foster ® NEXThaler ® drug particles emitted by dry powder inhalers with and without BAM have been measured by a Next Generation Impactor. Three characteristic inhalation profiles of asthmatic patients (low, moderate and high flow rates) were used for both experimental and modelling purposes. Particle hygroscopic growth was determined by a new method, where experimental measurements are combined with simulations. Upper airway and lung deposition fractions were computed assuming 5s and 10s breath-hold times. By the inclusion of BAM the fine particle fraction of the steroid component increased from 24 to 30% to 47-51%, while that of bronchodilator from 25-34% to 52-55%. The predicted upper airway steroid and bronchodilator doses decreased from about 60% to 35-40% due to BAM. At the same time, predicted lung doses increased from about 20%-35% (steroid) and from 22% to 38% (bronchodilator) for the moderate flow profile and from about 25% to 40% (steroid) and from 29% to 47% (bronchodilator) for the high inhalation flow profile. Although BDP and FF upper airway doses decreased by a factor of about two when BAM was present, lung doses of both components were about the same in the BAM and no-BAM configurations at the weakest flow profile. However, lung dose increased by 2-3% even for this profile when hygroscopic growth was taken into account. In conclusion, the NEXThaler ® BAM mechanism is a unique feature enabling high emitted fine particle fraction and enhanced drug delivery to the lungs., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Currently, all commercial available nebulized salbutamol in China is in its racemic form. It is known that only R-salbutamol (eutomer) has therapeutic effects, while S-salbutamol (distomer) may exacerbate asthma after chronic use. Therefore, it is an unmet clinical need to develop R-salbutamol as a nebulized product that is more convenient for young and old patients. In our study, a stable aerosol solution of R-salbutamol sulfate was established, and its antiasthmatic effects were confirmed. The decomposition rate and racemization effect of the R-salbutamol sulfate solution were evaluated over a pH range from 1 to 10 (except pH=7, 8) at 60°C. The aerodynamic particle size of the R-salbutamol sulfate solution and commercial RS-salbutamol sulfate solution were both tested in vitro by Next-Generation Impactor (NGI) in 5°C. Laser diffractometer was used to characterize the droplet-size distribution (DSD) of both solutions. We next conducted an in vivo animal study to document the antiasthmatic effect of R-salbutamol aerosol sulfate solution and determine the relationship to RS-salbutamol. The results showed that the R-salbutamol sulfate solution was more stable at pH 6. In vitro comparison studies indicated that there was no distribution difference between R-salbutamol sulfate solution and the commercial RS-salbutamol solution. The animal results showed that R-salbutamol was more potent than RS-salbutamol against the same dose of histamine challenge. Unlike commercial RS-salbutamol, which was acidified to a pH of 3.5 to extend bench life but may cause bronchoconstriction in asthmatic patients, the neutralized R-salbutamol solution was more suitable for clinic use.

Increasing evidence suggests Organic Cation Transporters (OCT) might facilitate the absorption of inhaled bronchodilators, including salbutamol, across the lung epithelium. This is essentially scarred and inflamed in asthma. Accordingly, the impact of epithelial insults relevant to asthma on OCT expression and salbutamol transport was evaluated in air-liquid interfaced layers of the human broncho-epithelial cell line Calu-3. These were physically injured and allowed to recover for 48h or exposed to the pro-inflammatory stimulant lipopolysaccharide (LPS) for 48h and the aeroallergen house dust mite (HDM) for 8h twice over 48h. Increases in transporter expression were measured following each treatment, with the protein levels of the OCTN2 subtype consistently raised by at least 50%. Interestingly, OCT upregulation upon LPS and HDM challenges were dependent on an inflammatory event occurring in the cell layers. Salbutamol permeability was higher in LPS exposed layers than in their untreated counterparts and in both cases, was sensitive to the OCT inhibitor tetraethylammonium. This study is the first to show epithelial injury, inflammation and allergen abuse upregulate OCT in bronchial epithelial cells, which might have an impact on the absorption of their substrates in diseased lungs., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: The asthmatic patient's respiratory tract deposition of HFA fluticasone (Flovent HFA(™)) has not been established. There is a known large particle size difference with another commercial inhaled HFA steroid (QVAR(™)). This study compared the 2D and 3D respiratory tract deposition of each inhaled steroid., Methods: This study was an open label, crossover study in eight patients diagnosed with asthma. The regional respiratory and oropharyngeal deposition of the two steroids were compared and contrasted using planar and SPECT imaging following delivery of the (99m)Tc-radiolabeled drug in each product. The SPECT images were merged with computed tomography images to quantify regional deposition within the patients., Results: Two-dimensional (2D) planar images indicated that 24% of the Flovent HFA dose and 55% of the QVAR dose deposited in the lungs. 2D oropharyngeal deposition indicated that 75% of the Flovent HFA dose was deposited in the oropharynx, while 42% of the QVAR dose deposited in the oropharynx. Three-dimensional (3D) SPECT data indicated that 22% of the Flovent HFA dose and 53% of the QVAR dose deposited in the lungs. 3D oropharyngeal and gut deposition indicated 78% of the Flovent HFA dose was deposited in the oropharynx, while 47% of the QVAR dose deposited in the oropharynx. The increased lung deposition and decreased oropharynx deposition for both 2D and 3D image data of QVAR were statistically different from Flovent HFA., Conclusions: QVAR exhibited a significant increase in lung delivery compared to Flovent HFA. Conversely, QVAR delivered a significantly lower dose to the oropharynx than Flovent HFA. The findings were presumed to be driven by the smaller particle size of QVAR (0.7 microns MMAD) compared with Flovent HFA (2.0 microns MMAD).

Background: Dry powder inhaler (DPI) users frequently exhale into their inhaler mouthpiece before the inhalation step. This error in technique compromises the integrity of the drug and results in poor bronchodilation. This study investigated the effect of four exhalation factors (exhalation flow rate, distance from mouth to inhaler, exhalation duration, and relative air humidity) on dry powder dose delivery. Given that acoustic energy can be related to the factors associated with exhalation sounds, we then aimed to develop a method of identifying and quantifying this critical inhaler technique error using acoustic based methods., Methods: An in vitro test rig was developed to simulate this critical error. The effect of the four factors on subsequent drug delivery were investigated using multivariate regression models. In a further study we then used an acoustic monitoring device to unobtrusively record the sounds 22 asthmatic patients made whilst using a Diskus(™) DPI. Acoustic energy was employed to automatically detect and analyze exhalation events in the audio files., Results: All exhalation factors had a statistically significant effect on drug delivery (p<0.05); distance from the inhaler mouthpiece had the largest effect size. Humid air exhalations were found to reduce the fine particle fraction (FPF) compared to dry air. In a dataset of 110 audio files from 22 asthmatic patients, the acoustic method detected exhalations with an accuracy of 89.1%. We were able to classify exhalations occurring 5 cm or less in the direction of the inhaler mouthpiece or recording device with a sensitivity of 72.2% and specificity of 85.7%., Conclusions: Exhaling into a DPI has a significant detrimental effect. Acoustic based methods can be employed to objectively detect and analyze exhalations during inhaler use, thus providing a method of remotely monitoring inhaler technique and providing personalized inhaler technique feedback.

Background: Suppression of small airway inflammation may contribute to achieving asthma control. We aimed to evaluate the additional effect of beclometasone dipropionate/formoterol (BDP/F) hydrofluoroalkane (HFA) pressurized metered dose inhaler (pMDI) (BDP/F-HFA 100/6 μg pMDI) on airway inflammation and functional parameters in asthma cases, who were optimally controlled by maintenance therapy., Methods: Ninety-five controlled asthmatic patients were included. They were grouped as Group 1 [budesonide/formoterol 320/9 μg dry powder inhaler (DPI)] and Group 2 (fluticasone/salmeterol 500/50 μg DPI) according to the combination they used. Then Group 3 was established by random selection from these two groups, and BDP/F-HFA 100/6 μg pMDI treatment was prescribed. All patients were evaluated in the beginning of the study and were re-evaluated at the end of a 3-week treatment period by spirometry, exhaled nitric oxide (eNO) levels, and small airway functional indices, namely, Sacin and Scond values., Results: There was no significant statistical difference in terms of age, height, weight, disease duration, symptoms, and spirometric parameters between the groups. There was a significant decrease in eNO levels in asthma cases who were on BDP/F-HFA therapy (p=0.001). A significant improvement in Sacin values at the end of the treatment period was observed in cases treated with BDP/F-HFA (p=0.001), indicating that inflammation was suppressed in peripheral airways., Conclusions: These results emphasize that asthma treatment has mainly focused on the strategy to keep the disease under control; maintaining optimal functional level might be underestimated. BDP/F-HFA may have an additional favorable effect on the peripheral airway inflammation in the controlled asthma.

There is an enormous drive to refine therapeutic designs and delivery systems, but in this review we ask if this is always the right direction? We choose to play devil's advocate, and argue that refining drug design is not always needed, and what is actually needed is a greater understanding of the biology of the disease. Here we focus on asthma and the β2-agonist group of bronchodilators as an example of how a class of therapeutic has been developed and continues to be developmentally refined. In this review, we define viral-induced exacerbations as the greatest cause of lung attacks and the most crucial time β2-agonist therapy is needed. We explore the reasons why β2-agonist therapy fails in patients with rhinovirus-induced exacerbations, and explain why further "engineered" β2-agonist therapies are likely to continue to fail in this subset of asthmatic population. We justify our perspective by returning to the biology that underlies the cause of disease and highlight the need for "more research" into alternative therapies for this population of asthmatic patients.

Salbutamol forms an important and widely administered β2 agonist prescribed in the symptomatic treatment of bronchial asthma. Unfortunately, a subset of patients show refractoriness to it owing to ADRB2 gene variant (rs 1800888). The variant substitutes Thr to Ile at the position 164 in the β2 adrenergic receptor leading to sub-optimal binding of agonists. The present study aims to associate the Salbutamol response with the variant and select the bioactive conformer of Sabutamol with optimal binding affinity against mutated receptor by in silico approaches. To assess bronchodilator response spirometry was performed before and 15 min after Salbutamol (200 mcg) inhalation. Responders to Salbutamol were categorized if percentage reversibility was greater than or equal to 12%, while those showing FEV₁ reversibility less than 12% were classified as non-responders. Among the 344 subjects screened, 238 were responders and 106 were non-responders. The frequency of mutant allele "T" was significantly higher in case of non-responders (p < 0.05). In silico process involved generation of Salbutamol conformer ensembles supported by systematic search algorithm. 4369 conformers were generated of which only 1882 were considered bioactive conformers (threshold RMSD≤1 in reference to normalized structure of salbutamol). All the bioactive conformers were evaluated for the binding affinity against (Thr164 Ile) receptor through MolDock aided docking algorithm. One of the bioactive conformer (P.E. = -57.0038, RMSD = 0.6) demonstrated 1.54 folds greater affinity than the normal Salbutamol in the mutated receptor. The conformer identified in the present study may be put to pharmacodynamic and pharmacokinetic studies in future ahead.

β(2)-Adrenoceptor (β(2)-AR) agonists are powerful bronchodilators and play a pivotal role in the management of pulmonary obstructive diseases, such as asthma and chronic obstructive pulmonary disease. Although these agents first were used many years ago, progress in drug development has resulted in better tolerated, long-acting β(2)-AR agonists (LABAs), such as formoterol and salmeterol. Although LABAs have been on the market for several years, relatively little is known on the rationale(s) behind their long duration of action. In this study, we focused on olodaterol (previously known as BI1744CL), a novel inhaled LABA, which provides a bronchodilating effect lasting 24 h and is currently in Phase III clinical trials. To understand the rationale behind its long duration of action, different aspects of olodaterol were analyzed (i.e., its lipophilicity and propensity to accumulate in the lipid bilayer as well as its tight binding to the β(2)-AR). In line with its physicochemical properties, olodaterol associated moderately with lipid bilayers. Instead, kinetic as well as equilibrium binding studies indicated the presence of a stable [(3)H]olodaterol/β(2)-AR complex with a dissociation half-life of 17.8 h due to ternary complex formation. The tight binding of olodaterol to the human β(2)-AR and stabilization of the ternary complex were confirmed in functional experiments monitoring adenylyl cyclase activity after extensive washout. Taken together, binding, kinetic, and functional data support the existence of a stable complex with the β(2)-AR that, with a dissociation half-life >17 h, might indeed be a rationale for the 24-h duration of action of olodaterol.

Introduction: Asthma and chronic obstructive pulmonary disease (COPD) are inflammatory disorders that have an increasing prevalence and associated morbidity and mortality. β(2)-adrenoceptor agonists (β(2)-agonists) act by stimulating the β(2)-adrenoceptor present on airway smooth muscle and other cells in the airway, resulting in bronchodilatation. β(2)-agonists are among the most commonly used drugs in the world and remain pivotal in the treatment of symptoms in patients with asthma and COPD. Salbutamol is a chiral drug with (R)- and (S)- isomers. Almost all β(2)-agonists that are used at present are racemic mixtures of (R)- and (S)-salbutamol., Areas Covered: In this review the authors show that (R)-salbutamol alone (generically known as levosalbutamol) provides beneficial β(2)-agonist effects at a cellular level and in experimental models of airways disease. In addition the authors demonstrate that (S)-salbutamol opposes the desirable effects of (R)-salbutamol and can actually cause features of asthma and COPD in vitro and in experimental asthma., Expert Opinion: Despite this strong body of experimental evidence, (R)-salbutamol has not shown consistent superiority over (S)- or racemic salbutamol in human asthma or COPD., (© 2011 Informa UK, Ltd)

Background: Inhaled short acting β2-agonists (SABA), e.g. albuterol, are used for quick reversal of bronchoconstriction in asthmatics. While SABA are not recommended for maintenance therapy, it is not uncommon to find patients who frequently use SABA over a long period of time and there is a suspicion that long term exposure to SABA could be detrimental to lung function. To test this hypothesis we studied the effect of long-term inhaled albuterol stereoisomers on immediate allergic response (IAR) and airway hyperresponsiveness (AHR) in mouse models of asthma., Methods: Balb/C mice were sensitized and challenged with ovalbumin (OVA) and then we studied the IAR to inhaled allergen and the AHR to inhaled methacholine. The mice were pretreated with nebulizations of either racemic (RS)-albuterol or the single isomers (S)- and (R)-albuterol twice daily over 7 days prior to harvest., Results: We found that all forms of albuterol produced a significant increase of IAR measured as respiratory elastance. Similarly, we found that AHR was elevated by albuterol. At the same time a mouse strain that is intrinsically hyperresponsive (A/J mouse) was not affected by the albuterol isomers nor was AHR induced by epithelial disruption with Poly-L-lysine affected by albuterol., Conclusions: We conclude that long term inhalation treatment with either isomer of albuterol is capable of precipitating IAR and AHR in allergically inflamed airways but not in intrinsically hyperresponsive mice or immunologically naïve mice. Because (S)-albuterol, which lacks affinity for the β2-receptor, did not differ from (R)-albuterol, we speculate that isomer-independent properties of the albuterol molecule, other than β2-agonism, are responsible for the effect on AHR.

Background: Nonasthmatic eosinophilic bronchitis (NAEB) and cough variant asthma (CVA) are common causes of chronic cough. Both are characterized by eosinophilic inflammation in the airways. However, airway hyperresponsiveness, which is a characteristic feature of CVA, is not observed in NAEB. We hypothesized that endogenous bronchodilator S-nitrosothiol (SNO) levels are different between patients with NAEB and CVA., Methods: SNO concentrations in sputum supernatant were measured using a commercially available kit in 20 NAEB and 21 CVA patients., Results: The mean sputum eosinophil counts and exhaled nitric oxide values were similar in patients with NAEB (12.4 ± 2.3%, 80.6 ± 8.1 ppb) and CVA (15.3 ± 3.7%, 97.7 ± 9.2 ppb). By contrast, SNO levels in the airway lining fluid of NAEB patients were substantially higher than those of CVA patients (87.1 ± 9.8 vs. 46.8 ± 4.8 μM; p < 0.05)., Conclusions: SNOs may be an important factor in determining the development of airway hyperresponsiveness in the presence of eosinophilic inflammation., (Copyright © 2011 S. Karger AG, Basel.)

Salbutamol patches were prepared and evaluated. The effect of different Eudragits and various plasticizers on the properties of the patches were studied. Patches were prepared by casting method employing different plasticizers. These patches were evaluated for weight, thickness uniformity, swelling index, tensile strength, elongation percent and moisture absorption capacity. Release was studied. Tensile strength of the patches using Eudragit RS 100 as well as RS100 + L100 and triacetin was the lowest. Formulae containing 10% oleic acid and 5% dimethyl formamide, respectively, showed the highest permeability. These two formulae were studied clinically, the first formula only showed a significant improvement.

Background: Racemic (R,S)-albuterol is a 1:1 mixture of an R-enantiomer which has bronchodilatory and anti-inflammatory effects, and an S-enantiomer which is associated with increased airway hyperreactivity and proinflammatory effects. Proinflammatory effects of regularly inhalated and S-albuterol have not been studied in a whole-animal model. We hypothesized that regular administration of R,S-albuterol or S-albuterol, but not R-albuterol, would induce airway inflammation in healthy and asthmatic cats., Methods: Six healthy and 5 experimentally asthmatic cats were randomized to receive inhaled R,S-albuterol, S-albuterol, R-albuterol, or placebo (saline) twice daily for 2 weeks, followed by a 6-week washout before crossover to the next treatment. Bronchoalveolar lavage fluid was collected for cell counts and cytokine analysis prior to and at the end of each 2-week treatment., Results: Healthy and asthmatic cats receiving R,S- and S-albuterol had higher total lavage cell numbers (p = 0.04 and p = 0.02, respectively) than those receiving R-albuterol and placebo. The number of lavage eosinophils and the TNF-alpha bioactivity was higher in asthmatic cats receiving R,S- and S-albuterol compared with those receiving the other treatments (p = 0.03 and p = 0.004, respectively). In healthy cats, the number of lavage neutrophils was higher when they received R,S- and S-albuterol compared with other treatments (p = 0.04)., Conclusion: Airway inflammation is induced in both healthy and asthmatic cats with regular inhalation of racemic and S-albuterol, but not with R-albuterol., (Copyright 2009 S. Karger AG, Basel.)

Background and Objective: Combined therapy with inhaled corticosteroids (ICSs) and long-acting beta(2)-adrenoceptor agonists (LABAs) is the recommended approach for the treatment of patients with asthma that is uncontrolled on ICSs alone. Additional studies are needed to assess the safety and efficacy of combination treatment with ICSs and LABAs in patients with mild asthma. The aim of this study was to compare the efficacy and tolerability of once-daily salmeterol/fluticasone propionate combination (SFC) with once-daily fluticasone propionate (FP) over a 12-week treatment period in patients with mild persistent asthma., Methods: This was a randomized, double-blind, placebo-controlled, parallel-group, multicentre study carried out in primary care or at a hospital outpatient department and included patients 12-79 years of age with mild persistent asthma (n = 458). After a 2-week run-in period, patients were randomized to receive SFC 50 microg/100 microg (n = 149), FP 100 microg (n = 154) or placebo (n = 155) once daily in the morning for 12 weeks. The primary efficacy endpoint was patient-recorded pre-dose mean morning peak expiratory flow (PEF). Other assessments included asthma symptom scores, use of rescue medication and investigator-recorded exacerbations. Lung function was measured and assessed during clinic visits., Results: For the primary efficacy endpoint of mean change in morning PEF, SFC achieved significantly greater increases from baseline than both placebo (difference in adjusted means 23 L/min; 95% CI 15.0, 30.3; p < 0.001) and FP (difference in adjusted means 14 L/min; 95% CI 6.3, 21.7; p < 0.001). Compared with those who received FP, patients in the SFC group demonstrated significantly greater improvements in mean evening PEF (95% CI 11.7, 28.1; p < 0.001), forced expiratory volume in 1 second (95% CI 0.093, 0.257; p < 0.001), forced expiratory flow between 25% and 75% of forced vital capacity (95% CI 0.242, 0.617; p < 0.001), the percentage of symptom-free days (95% CI 0.34, 0.87; p = 0.011), and the percentage of rescue medication-free days (95% CI 0.34, 0.90; p = 0.018). During weeks 5-12, 52% of patients in the SFC group achieved 'well controlled' asthma, compared with 42% and 26% of patients in the FP and placebo groups, respectively. Only one patient (receiving placebo) had a severe asthma exacerbation during the study; the frequency of adverse events was similar across the three treatment groups., Conclusion: Once-daily SFC 50 microg/100 microg provided significantly greater improvements in lung function and in asthma symptoms than once-daily FP 100 microg alone in patients with mild persistent asthma. However, twice-daily treatment with either SFC or ICSs plus short acting beta(2)-adrenoceptor agonists could be required to achieve guideline-defined asthma control in some patients.

Background: The National Heart, Lung, and Blood Institute guideline recommends that dosing racemic albuterol be administered every 1 to 4 hours for treating patients with asthma or chronic obstructive pulmonary disease (COPD) in the hospital. Previously published preliminary and retrospective studies suggested that levalbuterol can be administered every 8 hours for the treatment of bronchoconstriction in hospitalized patients. However, it is unclear how the different dosing regimens affect the total number of nebulizations (scheduled plus as-needed treatments) and the costs of treatment of bronchoconstriction in a hospital setting. Moreover, it is not clear how the different dosing regimens affect symptom outcomes and health status in hospitalized patients with asthma or COPD., Objective: The aim of this study was to evaluate these issues in hospitalized patients with acute asthma or COPD., Methods: In this prospective, multicenter, randomized, open-label study, hospitalized patients aged > or = 18 years were randomly assigned to receive 14-day treatment with levalbuterol 1.25 mg q6-8h or racemic albuterol 2.5 mg q1-4h, administered per routine hospital practice at each institution. The primary efficacy end point was total number of nebulizations during hospitalization. Pulmonary function, symptom evaluation (subject general well-being score [SGWB], disease symptom assessment [DSA], and beta-mediated adverse effect scores), hospital costs (excluding medication costs) and hospital length of stay (LOS) were also evaluated., Results: In the intent-to-treat population (n = 479; levalbuterol, 241;racemic albuterol, 238), the mean (SE) age was 55.3 (16.9) years, the majority of patients were white (57.8%), and the mean (SE) weight was 80.9 (24.5) kg. Demographic characteristics were similar between the 2 treatment groups, except that there were more females with COPD in the levalbuterol treatment group (63.88%) compared with the racemic albuterol treatment group (45.5%) (P = 0.005). Patients treated with levalbuterol required significantly fewer median total nebulizations (10 vs 12; P = 0.031) and scheduled nebulizations (9 vs 11; P = 0.009) compared with those in the racemic albuterol group. The 2 treatment groups required 0 rescue nebulizations. Mean (SD) forced expiratory volume in 1 second improved from baseline with both levalbuterol and racemic albuterol (0.06 [0.43] and 0.10 [0.37] L, respectively); these improvements were maintained throughout the hospital stay (0.11 [0.48] and 0.16 [0.52] L). DSA and SGWB scores improved significantly from baseline in both treatment groups, and beta-mediated adverse effects mean scores were significantly greater with levalbuterol versus racemic albuterol (P < 0.001). In the levalbuterol and racemic albuterol treatment groups, hospital LOS (70.6 and 65.7 hours, respectively), time to discharge (66.0 and 62.8 hours), and total hospital costs (least squares mean [SE], US $4869.30 [$343.58] and $4899.41 [$343.20]) were similar., Conclusions: In these hospitalized patients with acute asthma or COPD treated with levalbuterol every 6 to 8 hours or racemic albuterol every 1 to 4 hours, significantly fewer total nebulizations were required with levalbuterol, without an increased need for rescue nebulizations during 14 days of hospitalization. Both treatments were associated with improvements from baseline in symptoms and health status. The costs of treating bronchoconstriction in hospitalized patients were similar between the levalbuterol and racemic albuterol groups.

Background: Soy lecithin is widely used as an emulsifier, not only in topical skin care products but also in various drugs administered either topically, orally, or intravenously or by inhalation. Patients strongly allergic to soy and/or peanuts can develop an anaphylactic reaction when exposed to soy lecithin., Method: We report a 3-year-old asthmatic boy, allergic to peanuts, who was treated at the emergency department for an exacerbation of asthma following an upper respiratory tract infection. Within an hour after receiving the second of two inhalations of an ipratropium bromide (Atrovent) metered dose inhaler, he developed respiratory distress and generalized urticaria, an adverse event that regressed within 48 hours of withdrawal of the suspected drug. Soy lecithin, contained as an excipient in the metered dose inhaler, was strongly suspected of being responsible for this reaction., Conclusion: Drug products containing soy lecithin can cause severe allergic reactions in patients allergic to peanuts or soy. Physicians should be aware that adverse drug reactions can be due to both the active medical component and the excipient ingredients.

Asthma is a serious global health problem. People of all age groups in all countries of the world suffer from this chronic disease of the respiratory tract, which may have a very serious and sometimes fatal course. Most beta2-mimetics with a rapid onset of effect act for 4 to 6 hours. Inhalatory beta2-mimetics with long-term action (LABA), formoterol and salmeterol, possess a period of action longer than 12 hours. Formoterol and salmeterol represent great progress in asthma management, particularly in combination with inhalatory corticosteroids (IKS). Their effective bronchodilatory properties and long-term improvement of pulmonary functions are a great clinical contribution for the patients. Both formoterol and salmeterol are strong and effective beta2-agonists, but their different chemical structures produce different pharmacological properties. Due to the fact that the onset of the effect of salmeterol is slower, it should not be used to treat acute symptoms or quickly deteriorating asthma. Formoterol exerts a rapid onset of the effect and high internal activity, thanks to which it can be used for relieving treatment. The present paper aims to characterize and compare the properties of long-term acting beta2-mimetics, with detailed focus on their two representatives, formoterol and salmeterol.

With the exception of levosalbutamol, all of the beta2-agonists that are currently in use are racemic mixtures that are composed in equal amounts of (R)- and (S)-enantiomers. Clinical and mechanistic studies have demonstrated that (R)-salbutamol alone provides the beta2-agonist activity that is needed for the relief of bronchoconstriction, as well as the beta2-adrenergically mediated side effects. (S)-Salbutamol, on the other hand, has minimal binding affinity for the beta2-receptor, indicating that its effects are likely to be mediated through another site. Furthermore, there is evidence that (S)-salbutamol opposes the desirable effects of (R)-salbutamol in the racemic mixture and contributes to the development of characteristic features of asthma, such as airway obstruction, bronchial hyperresponsiveness and airway inflammation. Evidence from clinical studies shows delayed recovery from exacerbation of asthma by patients who are exposed to high concentrations of (S)-salbutamol.

Rationale: Aerosol particle size influences the extent, distribution, and site of inhaled drug deposition within the airways., Objectives: We hypothesized that targeting albuterol to regional airways by altering aerosol particle size could optimize inhaled bronchodilator delivery., Methods: In a randomized, double-blind, placebo-controlled study, 12 subjects with asthma (FEV1, 76.8 +/- 11.4% predicted) inhaled technetium-99m-labeled monodisperse albuterol aerosols (30-microg dose) of 1.5-, 3-, and 6-microm mass median aerodynamic diameter, at slow (30-60 L/min) and fast (> 60 L/min) inspiratory flows. Lung and extrathoracic radioaerosol deposition were quantified using planar gamma-scintigraphy. Pulmonary function and tolerability measurements were simultaneously assessed. Clinical efficacy was also compared with unlabeled monodisperse albuterol (15-microg dose) and 200 microg metered-dose inhaler (MDI) albuterol., Results: Smaller particles achieved greater total lung deposition (1.5 microm [56%], 3 microm [50%], and 6 microm [46%]), farther distal airways penetration (0.79, 0.60, and 0.36, respective penetration index), and more peripheral lung deposition (25, 17, and 10%, respectively). However, larger particles (30-microg dose) were more efficacious and achieved greater bronchodilation than 200 microg MDI albuterol (deltaFEV1 [ml]: 6 microm [551], 3 microm [457], 1.5 microm [347], MDI [494]). Small particles were exhaled more (1.5 microm [22%], 3 microm [8%], 6 microm [2%]), whereas greater oropharyngeal deposition occurred with large particles (15, 31, and 43%, respectively). Faster inspiratory flows decreased total lung deposition and increased oropharyngeal deposition for the larger particles, with less bronchodilation. A shift in aerosol distribution to the proximal airways was observed for all particles., Conclusions: Regional targeting of inhaled beta2-agonist to the proximal airways is more important than distal alveolar deposition for bronchodilation. Altering intrapulmonary deposition through aerosol particle size can appreciably enhance inhaled drug therapy and may have implications for developing future inhaled treatments.

Background: Acute asthma is often treated with racemic albuterol, a 1:1 mixture of (R)-albuterol and (S)-albuterol. Levalbuterol is the single-isomer agent comprised (R)-albuterol, an active bronchodilator, without any effects of (S)-albuterol., Objective: To compare emergency department (ED) admission rates of patients presenting with acute asthma who were treated with either racemic albuterol or levalbuterol., Setting: Suburban community teaching hospital., Design: Retrospective observational case review., Methods: Emergency department patients presenting with acute asthma at 2 different sites were reviewed over 9- and 3-month consecutive periods. Outcome measures included ED hospital admission rate, length of stay, arrival acuity, and treatment costs. Patients were excluded if younger than 1 year or if no treatment of acute asthma was rendered., Results: Of the initial 736 consecutive cases, significantly fewer admissions (4.7% vs 15.1%, respectively; P = .0016) were observed in the levalbuterol vs racemic albuterol group. Of the subsequent 186 consecutive cases, significantly fewer admissions were also observed (13.8% vs 28.9%, respectively; P = .021) in the levalbuterol vs racemic albuterol group. Treatment costs were lower with levalbuterol mainly because of a decrease in hospital admissions., Conclusion: Levalbuterol treatment in the ED for patients with acute asthma resulted in higher patient discharge rates and may be a cost-effective alternative to racemic albuterol.

Background: Administration of inhaled medications via metered-dose inhaler (MDI) to pediatric patients younger than 4 years usually requires use of a holding chamber or spacer with an attached face mask., Objective: To determine the particle size distribution and overall dose of albuterol from the albuterol sulfate hydrofluoroalkane delivered in conjunction with 2 US-marketed valved holding chambers (VHCs) compared with the dose delivered via MDIs without VHCs., Methods: Cascade impaction methods with high-performance liquid chromatography were used to evaluate the fine particle mass (FPM) of albuterol administered without and with the use of 2 commercially available VHCs., Results: Particle size distributions for the 2 VHCs and the control were similar. The mean FPM values for the 2 VHCs and the control were 32, 28, and 30 microg, respectively. Statistical comparison of the FPM shows a similar profile when differences from the albuterol hydrofluoroalkane without a spacer were evaluated., Conclusions: In vitro results obtained under these test conditions demonstrate that all the FPM values for the VHCs tested were within 15% of the control range, a difference that is unlikely to be clinically meaningful. These results do not warrant a change in the recommended dose of albuterol hydrofluoroalkane administered when using the VHCs tested. The use of an MDI in conjunction with a VHC provides a reasonable therapeutic approach for administration of albuterol hydrofluoroalkane to young children and other patients who have difficulty administering the MDI alone.

Asthma is characterized by airway hyperresponsiveness, chronic inflammation, and airway remodeling, which may lead to progressive, irreversible lung damage. Liposomes have been used for the delivery of aerosolized asthma medications into the lungs. This method could facilitate sustained action of steroids while using only a fraction of the dosage and a less frequent dosing interval than conventional therapy. We describe the evaluation of the effect of budesonide encapsulated in sterically stabilized liposomes on lung inflammation and airway hyperreactivity in a mouse model of asthma. We outline the determination of markers implicated in the progression of asthma, including histopathology, eosinophil peroxidase activity in bronchoalveolar lavage, and airway hyperresponsiveness to methacholine. Weekly administration of budesonide in sterically stabilized liposomes results in a significant reduction in the total lung inflammation score, peripheral blood eosinophil counts, and the total serum IgE level, similar to that obtained with daily budesonide. Airway hyperresponsiveness to methacholine challenge decreases significantly in the group treated with weekly budesonide in sterically stabilized liposomes, while it does not decrease in the daily budesonide group.

Background: Chlorofluorocarbons (CFCs) have traditionally been used as propellants in pressurized metered-dose inhalers (pMDIs), which are often used to deliver drugs to the lungs for the treatment of reversible obstructive airways diseases. However, CFCs are harmful to the environment and need to be phased out. Hydrofluoroalkanes (HFAs), such as HFA-134a, represent a safe alternative to CFC propellants for use with pMDIs. Formoterol fumarate has been recently formulated in an HFA-134a-containing pMDI and is undergoing clinical testing with the aim of providing an effective, safe and environmentally-friendly alternative to currently existing formulations., Objectives: The study objective was to demonstrate the non-inferiority (clinical equivalence) of the HFA-134a-propelled formoterol pMDI versus the formoterol Aerolizer dry powder inhaler (DPI)., Methods: The study was a single dose, double-blind, double-dummy, randomized, placebo and reference product controlled, three-periods, crossover trial in 49 patients with moderate-to-severe stable asthma. The active treatments involved a single 12-microg dose of formoterol delivered from an HFA-134a-propelled pMDI and an Aerolizer DPI. The primary efficacy parameter was the average 12-hour forced expiratory volume in 1 s (FEV1), calculated as area under the 12-hour post-morning dose FEV1 time curve divided by time (hours)., Results: Mean 12-hour average FEV1 was 2.28 liters for placebo, 2.60 liters for formoterol pMDI and 2.60 liters for the formoterol DPI. Contrast analysis showed that the HFA-propelled formoterol pMDI was significantly superior to placebo in terms of 12-hour average FEV1. Further statistical analysis confirmed bronchodilation with the pMDI formoterol formulation which was clinically equivalent to that seen with the DPI formoterol formulation. All treatments were well tolerated., Conclusions: The bronchodilatory effect of a 12-microg dose of formoterol inhaled from a CFC-free, HFA-propelled pMDI is significantly superior to placebo and equivalent to a commercially available formoterol DPI.

Effective asthma control requires long-term (anti-inflammatory) controller medications for patients with mild-persistent to severe-persistent disease, and quick-relief bronchodilator medication for all patients with asthma to control intermittent symptoms of cough, wheeze, and bronchoconstriction, as well as acute exacerbations. For patients with chronic obstructive pulmonary disease, quick-relief and long-acting bronchodilators are primarily used in the maintenance and treatment of associated symptoms, including shortness of breath. For many years, the most widely used bronchodilator has been racemic (R, S)-albuterol, a short-acting beta2-adrenergic agonist, commonly dispensed as an inhaled aerosol or solution. Until the introduction of levalbuterol inhalation solution (Xopenex) in 1999, all marketed forms of albuterol (including Ventolin and Proventil brands) were racemic mixtures composed of a 1:1 ratio of (R)- and (S)-stereoisomers. Administered as a proportionally equivalent nebulized dose, levalbuterol [(R)-albuterol] provides greater bronchodilation than racemic albuterol and, in the appropriate clinical setting, offers the possibility for improving clinical outcomes in patients with asthma and other obstructive airway diseases. Additionally, levalbuterol can be given at lower doses than racemic albuterol to provide comparable bronchodilation, with the potential for reduced beta-mediated adverse effects in adults and children. Only since the past decade has the technology to separate stereoisomers become available, and thus the biologic activities of the albuterol stereoisomers had not been established. Binding studies have demonstrated that (R)-albuterol binds to the beta2-adrenergic receptor with a high affinity, whereas (S)-albuterol binds with 100-fold less affinity than (R)-albuterol. Other evaluations have suggested that (R)-albuterol possesses the bronchodilatory, bronchoprotective, and ciliary-stimulatory properties of racemic albuterol, while (S)-albuterol does not contribute beneficially to the therapeutic effects of the racemate and was originally assumed to be inert. However, preclinical evaluations have shown that (S)-albuterol has effects that work in opposition to (R)-albuterol and may diminish the therapeutic effects of (R)-albuterol.

In the treatment of asthma, the conventional measures used to monitor a patient's progress and health status do not address the impact of functional impairments associated with the disease that may affect the patient's daily life. Unlike those measures, health-related quality of life (HRQL) reflects the physical, psychological, and social difficulties a patient perceives on a day-to-day basis. This study was conducted to determine the effects of once-daily budesonide inhalation powder via the Pulmicort Turbuhaler on the HRQL in adult patients with asthma previously treated with other inhaled corticosteroids. A total of 184 patients 18 to 70 years of age who previously received inhaled corticosteroids were enrolled in this double-blind, placebo-controlled, parallel-group, multicenter study. Patients were randomly assigned to budesonide 400 microg once daily or to placebo for 12 weeks. Each patient's HRQL was assessed at randomization and at weeks 4 and 12 with the Asthma Quality of Life Questionnaire (AQLQ). More patients receiving budesonide than those receiving placebo reported statistically significant (P < or = .05) improvements in HRQL at weeks 4 and 12. With the exception of the domain pertaining to exposure to environmental stimuli, differences from placebo in overall AQLQ scores and individual domain scores were clinically important (> or = 0.5 units). In addition, 2.4 patients needed to be treated with once-daily budesonide for 1 patient to demonstrate clinically important improvement. Budesonide 400 microg administered once daily via the Pulmicort Turbuhaler provides statistically significant and clinically important HRQL benefit in adult patients with asthma previously receiving inhaled corticosteroids.

Objective: To determine whether levalbuterol resulted in fewer hospital admissions than racemic albuterol when used for treatment of acute asthma. Study design A randomized, double-blind, controlled trial was conducted in the emergency department (ED) and inpatient asthma care unit of an urban tertiary children's hospital. Children age 1 to 18 years (n=482) provided a total of 547 enrollments. Patients received a nebulized solution of either 2.5 mg racemic albuterol or 1.25 mg levalbuterol every 20 minutes (maximum six doses). Patients admitted to the asthma care unit were treated in a standardized fashion by using the same blinded drug assigned in the ED. Hospitalization rate was the primary outcome., Results: Hospitalization rate was significantly lower in the levalbuterol group (36%) than in the racemic albuterol group (45 %, P=.02). The adjusted relative risk of admission in the racemic group compared with the levalbuterol group was 1.25 (95% confidence interval, 1.01-1.57). Hospital length of stay was not significantly shorter in the levalbuterol group (levalbuterol, 44.9 hours; racemic albuterol, 50.3 hours; P=.63). No significant adverse events occurred in either group., Conclusions: Substituting levalbuterol for racemic albuterol in the ED management of acute asthma significantly reduced the number of hospitalizations.

Objective: Salbutamol is commonly delivered as a racemic mixture of pharmacologically active (R)-salbutamol and inactive (S)-salbutamol. This study investigated inactive (S)- and active (R)-salbutamol plasma levels and their relationship to dose in patients with severe asthma., Methods: Basic demographics, racemic-salbutamol dose in the preceding 24 h, lung function tests at baseline and 1 h, and a 10 mL plasma sample were obtained from subjects presenting to the Department of Emergency Medicine with acute asthma. Plasma determinations were carried out using an LC-MS assay with solid phase extraction., Results: All patients (n = 5) had detectable levels of drug in plasma with range of 0.9-7.7 and 4.7-27.4 ng/mL for (R)-salbutamol and (S)-salbutamol respectively. These were correlated to total racemic salbutamol dose. The range of the (S) : (R) ratio was 2.0-5.2, with (R)-salbutamol representing 16-33% of the total plasma concentration, which did not correlate with total salbutamol dose., Conclusion: Only a small fraction of total plasma salbutamol concentration was found to consist of active enantiomer in patients with an acute severe exacerbation of asthma actively undergoing treatment with racemic-salbutamol. As a result of the possible contribution of (S)-salbutamol to poor asthma control further enantioselective investigations are warranted in severe asthma.

Racemic salbutamol, a beta2-adrenoceptor agonist used for dilatation of airways, has recently been shown to induce lessened relaxation of bronchial smooth muscle and partial loss of bronchoprotection, seen as increased hyperresponsiveness, after regular treatment. The racemate undergoes stereo-selective disposition, giving higher plasma levels of S-salbutamol than that of bronchodilating R-salbutamol, thus raising S : R ratios after repeated administration. Our aim was to evaluate whether increased bronchial hyperresponsiveness (BHR) could be found even after 1 day of repeated salbutamol inhalations, with beta2-receptor-induced bronchial smooth muscle relaxation remaining and whether this would be associated with plasma levels of either enantiomer. Fifteen patients with stable asthma, aged 19-54 years, were included in a randomized, cross-over study. An indirect bronchial challenge method was used [voluntary isocapnic hyperventilation of cold air (IHCA)], and airway condition tested by means of impulse oscillometry. Racemic salbutamol was inhaled three times during a 6-h period. IHCA was performed and plasma concentrations of enantiomers were measured 4 h after the last dose. Tests were also performed without preceding drug treatment. beta2-Agonist-produced bronchial dilatation and protection persisted in the majority of the 15 patients 4 h after repeated inhalations of salbutamol during 1 day. In only two of the 15 patients we could trace increased BHR after salbutamol. Neither dilatation nor protection could be linked to plasma levels of either R- or S-salbutamol. The underlying mechanisms of BHR remain unknown and are dissociated from beta2-receptor-mediated dilatation.

Racemic albuterol, a commonly used bronchodilator, is an exact 50:50 mixture of two enantiomers, R- and S-albuterol. Concern regarding increased mortality associated with the use of this beta-2 (beta 2) agonist triggered the study of both of these enantiomers separately. In vitro studies suggest that the two enantiomers have different binding affinities for beta-adrenoreceptors, may exert opposing effects on inflammation, demonstrate different effects on mucocilary transport, and display differing pharmacokinetics. Clinical studies comparing both enantiomers are few, of short duration, and often in small patient populations, and their results vary. R-albuterol has greater bronchodilatory effects than the racemate and may have anti-inflammatory properties. S-albuterol has markedly less affinity for the beta-adrenoreceptor. It was found to cause bronchoconstriction in animal models, but neither bronchoconstrictive nor pro-inflammatory effects have been conclusively demonstrated in human studies. The data available at present, while suggestive, are insufficient to conclusively recommend R-albuterol over the racemate. Further basic research and investigations in humans comparing both enantiomers at increasing doses over longer time periods are required to clarify the precise roles of R- and S-albuterol., (Copyright 2002 Wiley-Liss, Inc.)

Background: It has been suggested that R-albuterol produces bronchodilation that is comparable with that of racemic albuterol (RS-albuterol) on a 4:1 dose-for-dose basis but systemic side effects on a 2:1 basis, implying better therapeutic ratio for R-albuterol., Objective: We sought to carefully compare the bronchodilating and systemic effects of R- and RS-albuterol by using a crossover study design., Methods: Twenty asthmatic patients (15.1%-28.7% FEV(1) reversibility) were given R-albuterol (6.25-1600 microg), S-albuterol (6.25-1600 microg), RS-albuterol (12.5-3200 microg), or placebo in a crossover, double-blind, placebo-controlled fashion. Cumulative doses were given with a Mefar dosimeter, and FEV(1), heart rate, and plasma K(+) levels were measured 20 minutes after each dose., Results: Both R- and RS-albuterol produced dose-related improvement in FEV(1) and, at higher doses, increased heart rate and decreased plasma K(+) levels. Neither placebo nor S-albuterol had any significant effect. Individual estimates of the potency ratio for R-albuterol/RS-albuterol were calculated and summarized across all subjects. The geometric mean potency ratio for effects on FEV(1) was 1.9 (95% CI, 1.3-2.8), on HR of 1.9 (95% CI, 1.3-2.9), and on K(+) level of 1.7 (95% CI, 1.3-2.1)., Conclusion: All pharmacologic effects of RS-albuterol reside with the R-enantiomer, and S-albuterol is clinically inactive. The R-albuterol/RS-albuterol potency ratios for local (FEV(1)) and systemic effects (heart rate and K(+)) are similar, suggesting a comparable therapeutic ratio for R-albuterol and RS-albuterol in asthmatic subjects.

The aerodynamic properties of 99mTc radiolabeled carrier-free terbutaline sulphate (TBS) have been thoroughly investigated following delivery by Turbuhaler (AstraZeneca Lund, Sweden). A full and detailed radiolabeling procedure is also reported. The in vitro radiolabel validation was performed to determine whether TBS radiolabeled in this way would be representative of the commercially available product Bricanyl Turbuhaler during clinical trials. The results indicated that variations in aerodynamic properties had been introduced and that the radiolabel would slightly underestimate the fine particle fraction of Bricanyl, but would nonetheless act as a suitable marker in vivo. Assumptions regarding the aerodynamic properties of doses likely to be received by clinical trial subjects were also examined. This has been achieved by extending the validation procedures beyond those usually reported to include dose number, time, and homogeneity dependent studies. It was found that doses extracted for testing purposes and simulated patient doses extracted shortly afterward had similar properties. Doses extracted 2 h after initial testing also had similar properties to the test doses. These results suggested that data from the test doses could be used for quality control purposes, would be representative of the doses to be received by clinical trial subjects, and that a short delay between initial testing and trial subject inhalation would be acceptable.

A new generation of bronchodilators is being developed for acute asthma management-single-isomer beta-agonists. These drugs consist only of the active bronchodilatory isomer (eutomer); they do not have the inactive and potentially harmful isomer (distomer) that is present in marketed racemic beta-agonists. Clinical studies comparing the effectiveness of (R)-albuterol (levalbuterol) with racemic albuterol established a strong rationale for using single-isomer beta-agonists in place of the racemic mixture: reduced dosages provide equivalent bronchodilatory effects with fewer beta-mediated side effects. Higher dosages achieve superior bronchodilation in episodes of severe asthma and may reduce costs of emergency department treatment.

Doxofylline (7-(1,3-dioxalan-2-ylmethyl) theophylline) is a novel xanthine bronchodilator which differs from theophylline in that it contains a dioxalane group in position 7. Similarly to theophylline, its mechanism of action is related to the inhibition of phosphodiesterase activities, but in contrast it appears to have decreased affinities towards adenosine A1 and A2 receptors, which may account for its better safety profile. The bronchodilating activities of doxofylline have been demonstrated in clinical trials involving patients with either bronchial asthma or chronic obstructive pulmonary disease. In contrast to other bronchodilators, experimental and clinical studies have shown that the drug is devoid of direct stimulatory effects. This may be of importance because the arrhythmogenic actions of bronchodilators may have a negative impact on the survival of patients with respiratory diseases.

Background: The administration of salbutamol is permitted only by inhalation by the International Olympic Committee (IOC) for the management of asthma and exercise-induced asthma in athletes. The establishment of criteria to distinguish between the (IOC) authorized use (inhaled) and the (IOC) prohibited use (oral) of salbutamol appeared possible using simultaneous evaluation of variables based on the concentration of nonconjugated enantiomers of salbutamol excreted in urine., Methods: Urine was collected from asthmatic and nonasthmatic swimmers who had received various preexercise doses of oral (five doses of 4 mg) or inhaled (two doses of 100 microgram) salbutamol. Urine was also obtained from subjects who had received the maximum dosage of inhaled salbutamol advisable for competing athletes to provide protection from exercise-induced asthma and treatment of asthma (1600 microgram in 24 h, 800 microgram being in the last 4 h). All samples were analyzed to determine the total amount of unchanged salbutamol excreted in urine and the ratio between the S: and R: enantiomers., Results: The discriminant function D = -3.776 + 1.46 x 10(-3) ([S:(+)] + [R:(-)]) + 1.012 ([S:(+)]/[R(-)]) can be used to classify data into two groups, inhaled and oral. The confirmatory criterion suggested (cutoff at D = 1.06, 4 SD from the mean D value of the inhaled distribution) has been verified in different sets of samples showing suspicious concentrations by conventional screening procedures in doping control. An 11.8% false-negative (oral classified as inhaled) rate is assumed with the confirmatory criterion proposed, but virtually no false positives (inhaled classified as oral) are obtained (<1 in 33 000)., Conclusions: The overall procedure recommended is to screen all samples and to apply the confirmation criterion proposed to samples showing free racemic salbutamol concentrations >500 microgram/L by gas chromatography-mass spectrometry or free + conjugated racemic salbutamol concentrations >1400 microgram/L by ELISA.

Although racemic albuterol is an effective bronchodilator, regular use has been associated with some loss of bronchodilator potency, decreased protection against bronchoprovocation, increased sensitivity to allergen challenge, and increased sensitivity to some bronchoconstrictor stimuli. In experimental animals racemic albuterol has produced bronchial hyperresponsiveness, which could also be induced by administration of (S)-albuterol. These findings suggest that the pure or homochiral formulation of (R)-albuterol (levalbuterol) might be more effective as a bronchodilator than the racemic form. Single doses of levalbuterol provided more prolonged protection against methacholine challenge than the racemate, whereas (S)-albuterol significantly increased sensitivity to methacholine. In a 4-week study in adults, equivalent amounts of pure levalbuterol provided greater bronchodilation than did similar amounts of levalbuterol given as racemic mixtures. Furthermore, after 4 weeks, the baseline morning FEV(1 ) was lower in those receiving the racemate than in those receiving placebo or levalbuterol. In a single-dose study in children, the same conclusion regarding greater bronchodilation with pure levalbuterol compared with the same amount of levalbuterol in a racemic mixture was confirmed. These studies appear to confirm the greater efficacy of pure levalbuterol over a similar amount in a racemic mixture. This implies a deleterious effect of (S)-albuterol on both the acute bronchodilator response and baseline airway caliber, the exact mechanism of which will require further investigation.

Racemic albuterol is composed of an equimolar mixture of stereoisomers. For asthma therapy, (R)-albuterol is the eutomer and (S)-albuterol is the distomer. By interacting with beta(2 )-adrenoceptors, (R)-albuterol has bronchodilator, bronchoprotective, anti-edematous properties and inhibits activation of mast cells and eosinophils. (S)-albuterol does not activate beta(2 )-adrenoceptors and does not modify activation of beta(2 )-adrenoceptors by (R)-albuterol so that for many years it was presumed to be biologically inert. Recently, it has been established that regular and excessive use of racemic albuterol induces paradoxical reactions in some subjects with asthma. Because such effects cannot be accounted for by activation of beta(2 )-adrenoceptors, the pharmacologic profile of (S)-albuterol has been more carefully defined. (S)-albuterol has distinctive pharmacologic properties that are unrelated to activation of beta(2 )-adrenoceptors. Thus, (S)-albuterol intensifies bronchoconstrictor responses of sensitized guinea pigs and induces hypersensitivity of asthmatic airways; it also promotes the activation of human eosinophils in vitro. These actions of (S)-albuterol may explain why racemic albuterol can intensify allergic bronchospasm and promote eosinophil activation in asthmatic airways. The capacity of (S)-albuterol to elevate intracellular Ca(2+) would account for the paradox because this action will oppose, or even nullify, the consequences of adenylyl cyclase activation by (R)-albuterol. Because (S)-albuterol is metabolized more slowly than (R)-albuterol and is retained preferentially within the airways, paradoxical effects become more prominent during regular and excessive use of racemic albuterol. Because (S)-albuterol has detrimental effects in asthmatic airways, levalbuterol [homochiral (R)-albuterol] should have advantages over racemic albuterol in therapy for asthma.

Background: Commercially available salbutamol is a racemic mixture consisting of equal amounts of the two enantiomers, R-salbutamol and S-salbutamol, felt to be active and inert, respectively., Methods: A double blind, randomised, four way, crossover study was performed in 12 well controlled asthmatic subjects (forced expiratory volume in one second (FEV1) > 70% predicted, no beta 2 agonists for > or = 4 weeks). Subjects were studied on four days at intervals of 48 hours to seven days. FEV1 was assessed before and both FEV1 and methacholine PC20 were measured 20 and 180 minutes after a single dose of nebulised racemic salbutamol 2.5 mg, R-salbutamol 1.25 mg, S-salbutamol 1.25 mg, and placebo., Results: Equivalent bronchodilation was seen for both R-salbutamol and racemic salbutamol (mean (SE) 12.4 (3.1)% and 12.0 (3.0)%, respectively, at 20 minutes and 5.9 (2.9)% and 5.2 (2.2)% at 180 minutes). The increase in FEV1 of 5.2 (0.9)% at 20 minutes and the decline in FEV1 of 2.9 (2.1)% at 180 minutes after S-salbutamol were not significantly different from the placebo response. Compared with placebo the methacholine PC20 after R-salbutamol and racemic salbutamol improved by 3.3 (95% CI 2.5 to 4.1) and 3.4 (95% CI 2.6 to 4.2) doubling doses, respectively, at 20 minutes and 1.2 (95% CI 0.6 to 1.8) and 1.0 (95% CI 0.2 to 1.8) doubling doses at 180 minutes. S-salbutamol resulted in an improvement of 0.9 (95% CI 0.3 to 1.5) doubling doses at 20 minutes and no change at 180 minutes. Restlessness (n = 11) and increased pulse were seen 20 minutes after racemic and R-salbutamol but not S-salbutamol or placebo, and not at 180 minutes. There were no other adverse events., Conclusion: A single dose of 1.25 mg nebulised R-salbutamol produced equivalent bronchoprotection, bronchodilation, restlessness, and tachycardia as did 2.5 mg of racemic salbutamol. S-salbutamol 1.25 mg had a weak bronchoprotective effect; this could be because of a small amount of contamination with R-salbutamol or because S-salbutamol is an intrinsically weak beta 2 receptor stimulant.