The impact of inhaler technique on clinical outcomes in adolescents and adults with asthma: A systematic review.

BACKGROUND: Many patients with asthma use their inhalers incorrectly, which can lead to sub-optimal asthma control and an increased risk of exacerbations. The Accuhaler/Diskus and Turbuhaler are arguably two of the most commonly used dry powder inhalers worldwide. METHODS: A systematic literature review (SLR) was conducted to assess the impact of inhalation errors with these dry powder inhalers on clinical outcomes in asthma. Database searches were conducted in MEDLINE, Embase and proceedings from scientific conferences. Observational studies in adults and adolescents with asthma, reporting data for Accuhaler/Diskus and Turbuhaler devices and at least one outcome of interest, were included. Dual-independent screening and validation of studies was performed. RESULTS: The search identified 35 studies. A range of inhaler errors was observed across studies and devices. In 8 out of the 9 studies that involved the two devices, the percentage of overall inhaler error rates was numerically (7 studies) or significantly (1 study) higher for Turbuhaler than Diskus, ranging from 3.7% to 71.9% for Diskus and 1.2%-83% for Turbuhaler. Critical errors, reported in three studies using similar definitions, ranged from 20% to 43% for Diskus and 32%-100% for Turbuhaler. Five studies reported a significant association between inhaler errors and worse asthma control, while one showed no difference. CONCLUSIONS: This SLR identified a large range of inhaler errors with both devices. Across devices, a better inhalation technique was associated with better asthma outcomes. This systematic review confirms the importance of patients using their inhalers correctly as an integral part of achieving optimal asthma outcomes.

Budesonide + formoterol delivered via Spiromax® for the management of asthma and COPD: The potential impact on unscheduled healthcare costs of improving inhalation technique compared with Turbuhaler®.

BACKGROUND: Fixed-dose combinations of inhaled corticosteroids and long-acting ß2 agonists are commonly used for the treatment of asthma and COPD. However, the most frequently prescribed dry powder inhaler delivering this medicine - Symbicort® (budesonide and formoterol, BF) Turbuhaler® - is associated with poor inhalation technique, which can lead to poor disease control and high disease management costs. A recent study showed that patients make fewer inhaler errors when using the novel DuoResp® (BF) Spiromax® inhaler, compared with BF Turbuhaler®. Therefore switching patients from BF Turbuhaler® to BF Spiromax® could improve inhalation technique, and potentially lead to better disease control and healthcare cost savings. METHODS: A model was developed to estimate the budget impact of reducing poor inhalation technique by switching asthma and COPD patients from BF Turbuhaler® to BF Spiromax® over three years in Germany, Italy, Sweden and the UK. The model estimated changes to the number, and associated cost, of unscheduled healthcare events. The model considered two scenarios: in Scenario 1, all patients were immediately switched from BF Turbuhaler® to BF Spiromax®; in Scenario 2, 4%, 8% and 12% of patients were switched in years 1, 2 and 3 of the model, respectively. RESULTS: In Scenario 1, per patient cost savings amounted to €60.10, €49.67, €94.14 and €38.20 in Germany, Italy, Sweden and the UK, respectively. Total cost savings in each country were €100.86 million, €19.42 million, €36.65 million and €15.44 million over three years, respectively, with an estimated 597,754, 151,480, 228,986 and 122,368 healthcare events avoided. In Scenario 2, cost savings totalled €8.07 million, €1.55 million, €2.93 million and €1.23 million over three years, respectively, with 47,850, 12,118, 18,319, and 9789 healthcare events avoided. Savings per patient were €4.81, €3.97, €7.53 and €3.06. CONCLUSIONS: We demonstrated that reductions in poor inhalation technique by switching patients from BF Turbuhaler® to BF Spiromax® are likely to improve patients' disease control and generate considerable cost savings through healthcare events avoided.

The economic burden of asthma and chronic obstructive pulmonary disease and the impact of poor inhalation technique with commonly prescribed dry powder inhalers in three European countries.

BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) are common chronic inflammatory respiratory diseases, which impose a substantial burden on healthcare systems and society. Fixed-dose combinations (FDCs) of inhaled corticosteroids (ICS) and long-acting ß2 agonists (LABA), often administered using dry powder inhalers (DPIs), are frequently prescribed to control persistent asthma and COPD. Use of DPIs has been associated with poor inhalation technique, which can lead to increased healthcare resource use and costs. METHODS: A model was developed to estimate the healthcare resource use and costs associated with asthma and COPD management in people using commonly prescribed DPIs (budesonide + formoterol Turbuhaler(®) or fluticasone + salmeterol Accuhaler(®)) over 1 year in Spain, Sweden and the United Kingdom (UK). The model considered direct costs (inhaler acquisition costs and scheduled and unscheduled healthcare costs), indirect costs (productive days lost), and estimated the contribution of poor inhalation technique to the burden of illness. RESULTS: The direct cost burden of managing asthma and COPD for people using budesonide + formoterol Turbuhaler(®) or fluticasone + salmeterol Accuhaler(®) in 2015 was estimated at €813 million, €560 million, and €774 million for Spain, Sweden and the UK, respectively. Poor inhalation technique comprised 2.2-7.7 % of direct costs, totalling €105 million across the three countries. When lost productivity costs were included, total expenditure increased to €1.4 billion, €1.7 billion and €3.3 billion in Spain, Sweden and the UK, respectively, with €782 million attributable to poor inhalation technique across the three countries. Sensitivity analyses showed that the model results were most sensitive to changes in the proportion of patients prescribed ICS and LABA FDCs, and least sensitive to differences in the number of antimicrobials and oral corticosteroids prescribed. CONCLUSIONS: The cost of managing asthma and COPD using commonly prescribed DPIs is considerable. A substantial, and avoidable, contributor to this burden is poor inhalation technique. Measures that can improve inhalation technique with current DPIs, such as easier-to-use inhalers or better patient training, could offer benefits to patients and healthcare providers through improving disease outcomes and lowering costs.

In vitro aerodynamic characterization of the dose emitted during nebulization of tobramycin high strength solution by novel and jet nebulizer delivery systems.

BACKGROUND: Chronic infections with Pseudomonas aeruginosa are a leading cause of morbidity in patients with cystic fibrosis (CF). The aim of tobramycin inhalation therapy in CF patients with chronic pulmonary infection is to deliver high amounts of drug directly to the site of infection. TOBI(®) is a tobramycin nebulizer solution (300 mg/5 ml) approved by FDA for maintenance therapy for patient with CF. The 20% tobramycin sulfate solution was reported as the optimal and maximal concentration. METHODS: Nebulization of high strength tobramycin solution (20% tobramycin sulfate) (HSTS) has been assessed in this study by using different selected high performance nebulizer delivery systems: two different designs of jet nebulizers, and three new nebulizers based on vibrating mesh technology. The aerosol particle size distribution and output characteristics were measured for in vitro performance assessment of the nebulizer systems. The methodology was adapted from the current European standard, EN 13544-1:2001E. RESULTS: The particle size distribution characteristic measurements showed that all tested nebulizers may be suitable for inhalation of HSTS. The mean (SD) of highest percentage of fine particles (<5 µm) was 77.64 (2.3) % for Sidestream(®), at flow rate 16 L/min. The highest respirable inhaled mass was for Pari LC Plus(®) combined with PariBoyN(®) compressor, with mean (SD) 90.85 (8.6) mg. The mean (SD) of highest drug wastage percentage was 63.9 (3.9) % for Sidestream(®) jet nebulizer combined with compressed air cylinder at flow rate 16 L/min, while the lowest was 2.3 (0.26) % for NE-U22 Omron(®) (high frequency). CONCLUSIONS: The HSTS can be nebulized by all tested nebulisers but the high frequency NE-U22 Omron(®) and Aeroneb Go(®) are more efficient. When the HSTS compared to TOBI(®), the respirable inhaled dose was increased to more than 73%.

Inhaler competence in asthma: common errors, barriers to use and recommended solutions.

Whilst the inhaled route is the first line administration method in the management of asthma, it is well documented that patients can have problems adopting the correct inhaler technique and thus receiving adequate medication. This applies equally to metered dose inhalers and dry powder inhalers and leads to poor disease control and increased healthcare costs. Reviews have highlighted these problems and the recent European Consensus Statement developed a call to action to seek solutions. This review takes forward the challenge of inhaler competence by highlighting the issues and suggesting potential solutions to these problems. The opportunity for technological innovation and educational interventions to reduce errors is highlighted, as well as the specific challenges faced by children. This review is intended as a policy document, as most issues faced by patients have not changed for half a century, and this situation should not be allowed to continue any longer. Future direction with respect to research, policy needs and practice, together with education requirements in inhaler technique are described.

Dose emission and aerodynamic characterization of the terbutaline sulphate dose emitted from a Turbuhaler at low inhalation flow.

Previously, dose emission below 30 L min(-1) through DPI has not been routinely determined. However, during routine use some patients do not achieve 30 L min(-1) inhalation flows. Hence, the aim of the present study was to determine dose emission characteristics for low inhalation flows from terbutaline sulphate Turbuhaler. Total emitted dose (TED), fine particle dose (FPD) and mass median aerodynamic diameter (MMAD) of terbutaline sulphate Turbuhaler were determined using inhalation flows of 10-60 L min(-1) and inhaled volume of 4 L. TED and FPD increase significantly with the increase of inhalation flows (p <0.05). Flows had more pronounced effect on FPD than TED, thus, faster inhalation increases respirable amount more than it increases emitted dose. MMAD increases with decrease of inhalation flow until flow of 20L min(-1) then it decreases. In vitro flow dependent dose emission has been demonstrated previously for Turbuhaler for flow rates above 30 L min(-1) but is more pronounced below this flow. Minimal FPD below 30 L min(-1) suggests that during routine use at this flow rate most of emitted dose will impact in mouth. Flow dependent dose emission results suggest that Pharmacopoeias should consider the use variety of inhalation flows rather than one that is equivalent to pressure drop of 4 KPa.

The Genuair® inhaler: a novel, multidose dry powder inhaler.

This article reviews the Genuair(®) inhaler, a novel, multidose, breath-actuated dry powder inhaler. The inhaler design includes visual and acoustic feedback to reassure patients that they have taken their medication correctly, a dose indicator and a lock-out mechanism to prevent the use of an empty inhaler. The inhaler has medium airflow resistance and uses an optimised dispersion system to ensure effective deagglomeration of the inhalation powder. In vitro studies have demonstrated that the inhaler delivers a reproducible aerodynamic aerosol quality and is reliable under various thermal and mechanical stress conditions. Further studies in vitro have demonstrated that the total emitted dose and fine particle dose are both consistent over a range of inhalation flows from 45 to 95 l/min, as well as being independent of inhalation volume (2 l vs. 4 l) and storage conditions. In healthy subjects, delivery of aclidinium bromide 200 µg via the inhaler achieved high lung deposition (approximately 30% of the metered dose). A further study has shown that patients with moderate or severe chronic obstructive pulmonary disease can generate sufficient inspiratory airflow through the inhaler to reliably inhale the full dose and reset the inhaler. The inhaler has been used to deliver aclidinium in many clinical trials and the available data indicate that it has high acceptability amongst patients.

The relative lung and systemic bioavailability of terbutaline following nebulisation in non-invasively ventilated patients.

Nebulising a bronchodilator during non-invasive ventilation (NIV) is effective but there is a lack of consensus on the system to use because comparator in vivo studies in these patients are difficult. Urinary pharmacokinetic methodology post inhalation could provide this information. Chronic obstructive pulmonary disease patients requiring NIV received randomised study doses of either 2mg terbutaline nebulised from an Aeroneb Pro (AERO) or 5mg from a Sidestream (SIDE) on days 1 and 3 of admission. Urine samples were provided at 30 min then pooled up to 24h post inhalation and amounts of urinary terbutaline (UTER0.5 and UTER24; indices of relative lung and systemic bioavailability, respectively) were determined. Twelve consenting patients receiving NIV mean (SD) age and weight of 74.8 (8.2) years and 61.0 (10.7)kg completed the study. The mean (SD) UTER0.5 following AERO and SIDE was 9.4 (3.7) and 10.4 (4.1) µg with a mean ratio (90% confidence interval) of 89.7 (87.8, 92.3)%. UTER24 was 192.3 (52.4) and 205.3 (58.0)mcg with a mean ratio (90% CI) of 93.7 (113.5, 77.3)%. This urinary pharmacokinetic method to identity relative lung and systemic bioavailability between two nebuliser systems was easy to perform and is a useful and simple in vivo method to compare different nebulisers in patients receiving non-invasive ventilation.

What the pulmonary specialist should know about the new inhalation therapies.

A collaboration of multidisciplinary experts on the delivery of pharmaceutical aerosols was facilitated by the European Respiratory Society (ERS) and the International Society for Aerosols in Medicine (ISAM), in order to draw up a consensus statement with clear, up-to-date recommendations that enable the pulmonary physician to choose the type of aerosol delivery device that is most suitable for their patient. The focus of the consensus statement is the patient-use aspect of the aerosol delivery devices that are currently available. The subject was divided into different topics, which were in turn assigned to at least two experts. The authors searched the literature according to their own strategies, with no central literature review being performed. To achieve consensus, draft reports and recommendations were reviewed and voted on by the entire panel. Specific recommendations for use of the devices can be found throughout the statement. Healthcare providers should ensure that their patients can and will use these devices correctly. This requires that the clinician: is aware of the devices that are currently available to deliver the prescribed drugs; knows the various techniques that are appropriate for each device; is able to evaluate the patient's inhalation technique to be sure they are using the devices properly; and ensures that the inhalation method is appropriate for each patient.

New HPLC assay for urinary salbutamol concentrations in samples collected post-inhalation.

A new reversed phase high performance liquid chromatography (HPLC) method with fluorescence detection and two solid phase extraction (SPE) methods have been developed, optimised and validated for determining salbutamol in human urine after an inhalation. SPE methodology for unchanged salbutamol (USAL) and salbutamol plus its metabolites (USALMET) concentrations in urine has been developed using terbutaline as the internal standard. Confirm HCX cartridges were used for USAL and Oasis HLB for USALMET. Calibration lines of salbutamol urine standards were linear over the range 25-300 microg/L with mean (RSD) r(2) values of 0.9983 (0.06%) for USAL and 0.9976 (0.202%) for USALMET. The HPLC method was accurate (mean bias -0.40% for USAL and 0.46% for USALMET) and precise (mean RSD 5.0% for USAL and 2.90% for USALMET). The calculated LOD and LOQ for salbutamol using a 1 mL urine sample were 4.0 and 12.12 microg/L for USAL, and 4.80 and 14.56 microg/L for USALMET, respectively. The mean (RSD) SPE recoveries of salbutamol were 90.82% (2.32%) for USAL and 91.54% (2.96%) for USALMET. Both HPLC and SPE methods were applied to quantify unchanged and metabolised salbutamol excreted in urine after the inhalation of 200 microg salbutamol from metered dose inhalers (MDIs) by 14 healthy volunteers. Charcoal slurries were also ingested to prevent gastro-intestinal absorption. Urine samples were collected at 30 min post-inhalation and then pooled for the next 24h. All urine concentrations were within the sensitive portion of the assay. The volunteer study revealed that following inhalation from an MDI about 20% of the nominal dose is deposited into the lungs and 46% is delivered to the systemic circulation. The results confirm the application, sensitivity, reliability and robustness of the HPLC and SPE methods for urinary pharmacokinetic studies after salbutamol inhalations using therapeutic doses.

Development and validation of HPLC method for the determination of tobramycin in urine samples post-inhalation using pre-column derivatisation with fluorescein isothiocyanate.

A reversed-phase liquid chromatography method involving pre-column derivatisation with fluorescein isothiocyanate (FITC, isomer I) for determination of tobramycin in urine samples after inhalation has been developed. FITC reacts with the primary amino groups of tobramycin and other aminoglycosides under mild conditions to form a highly fluorescent and stable derivative. The chromatographic separation was carried out on a Phenomenex Luna C(18) column at ambient temperature using a constant flow rate of 1 ml/min and mobile phase of acetonitrile-methanol-glacial acetic acid-water (420:60:5:515, v/v/v/v). The tobramycin-FITC derivative was monitored by fluorescent detection at an excitation wavelength 490 nm and emission wavelength 518 nm. The linearity of response for tobramycin was demonstrated at 11 different concentrations of tobramycin extracted from spiked urine, ranging from 0.25 to 20 microg/ml. Tobramycin and neomycin were extracted from spiked urine by a solid phase extraction clean-up procedure on a carboxypropyl-bonded phase (CBA) weak cation-exchange cartridge, and the relative recovery was >99% (n=5). The limit of detection (LOD) and limit of quantitation (LOQ) in urine were 70 and 250 ng/ml, respectively. The method had an accuracy of <0.2%, and intra-day and inter-day precision (in term of %coefficient of variation) were <4.89% and 8.25%, respectively. This assay was used for urinary pharmacokinetic studies to identify the relative lung deposition of tobramycin post-inhalation of tobramycin inhaled solution 300 mg/5 ml (TOBI) by different nebuliser systems.

The Diskus: a review of its position among dry powder inhaler devices.

The use of dry powder inhalers (DPIs) to administer treatments for respiratory diseases has increased significantly in recent years. There is now a wide range of DPIs available that vary considerably in design, required operational techniques, output characteristics and drug delivery across a range of inhalation patterns. Different patient populations may find individual types of DPI easier to use correctly than others and selecting the right DPI for particular patient requirements will improve compliance with therapy. For example, some DPIs offer a greater resistance against inspirational flow rate than others which affects the total emitted dose and also fine particle mass of the aerosol released. An individual patient may therefore receive different amounts of drug when inhaling from different DPIs. Therefore, it is important that the prescriber is fully aware of the characteristics of the different types of DPI, so that he or she can prescribe the device that is most appropriate to an individual patient's needs. This review explores the characteristics of currently available DPIs and evaluates their efficacy and patient acceptability. The differences in output characteristics, ease of use and patient preferences between available devices is shown to affect treatment efficacy and patient compliance with therapy. Changing the DPI prescribed to a patient to a cheaper or generic device may therefore adversely affect disease control and thereby increase the cost of treatment.

Validation of high-performance liquid chromatography assay for quantification of formoterol in urine samples after inhalation using UV detection technique.

A novel high-performance liquid chromatography (HPLC) assay for the estimation of formoterol in urine samples was developed and validated. A solid phase extraction (SPE) using Oasis HLB was optimised to isolate formoterol from a urine matrix followed by HPLC with UV detection. This extraction procedure concentrated the final analyte forty times so that UV detection can be used to determine even a low concentration of formoterol in urine samples. The urinary assay was performed in accordance with FDA and ICH regulations for the validation of bioanalytical samples. The samples were injected onto a C18 Spherisorb (250 mm x 4.6 mm x 5 microm) analytical column maintained at 30 degrees C. The mobile phase consisted of 5 mM of potassium dihydrogen orthophosphate buffer (adjusted to pH 3 with ortho phosphoric acid):acetonitrile (ACN) (70:30, v/v), and the formoterol peak was detected at wavelength 214 nm. The extraction recovery of formoterol from the urine sample was >95%. The calibration curve was linear (r2=0.99) over formoterol concentrations ranging from 1.5 to 25 ng/mL (n=6). The method had an accuracy of >92% and intra and inter-day precision CV% of <3.9% and <2.2%, respectively, at three different concentrations low, medium and high (10, 15, 20 ng/mL). The limit of quantification (LOQ) for formoterol was found to be 1.50 ng/mL. The accuracy and precision at the LOQ level were 95% and %CV <3.7% (n=10), respectively. The method reported is simple, reliable, precise, and accurate and has the capacity to be used for determination of formoterol in urine samples.

High performance liquid chromatography assay method for simultaneous quantitation of formoterol and budesonide in Symbicort Turbuhaler.

A sensitive and rapid high performance liquid chromatography method has been developed and used for the simultaneous determination of formoterol and budesonide in Symbicort Turbuhaler when assessing the aerodynamic characteristics of the emitted dose using Pharmacopoeial methods. This capability results in both time and cost saving. The mobile phase composition was acetonitrile-5 mM sodium dihydrogen orthophosphate, pH 3 (60: 40% v/v), and was passed at 1.5 ml min(-1) through a C18 column with a UV detection (wavelength 214 nm). The method was shown to give good analytical performance in terms of linearity, precision (using phenylpropanolamine as an internal standard), sensitivity and solution stability. The intra-day precision for both formoterol and budesonide were 0.75% and 1.11%, respectively (n = 10). The limit of quantitation for formoterol was 10 microgL(-1) and for budesonide was 120 microgL(-1), and the limit of detection were 3 and 30 microgL(-1), for both formoterol and budesonide, respectively. The method has been applied to determine the content of the emitted dose and the fine particle dose of Symbicort Turbuhaler.

Can patients use all dry powder inhalers equally well?

If patients are unable to use their inhaler, drug delivery may be unsatisfactory and the patients may fail to benefit from the prescribed medication. It is important to consider whether patients can use all dry powder inhalers equally well. Changing a patient from a dry powder inhaler used well to one that the patient is unable to operate effectively could compromise asthma control. The many marketed dry powder inhalers reflect differences in design decisions that could affect lung deposition. Studies using different dry powder inhalers have confirmed that different lung deposition patterns are observed. Furthermore, there may be considerable individual variability in lung deposition. Differences in lung deposition patterns could have clinical effects. Studies may show similar clinical effectiveness with two inhalers, because most products are used at the plateau phase of the dose-response curve, although there may be differences in the adverse event profile. The ideal inhaler does not yet exist. Different dry powder inhalers show some but not all features of the ideal inhaler; hence, patients may prefer some aspects of one inhaler while favouring a different inhaler for other features. The individual balance of features will govern the overall preference for one inhaler over others. The method for operation of dry powder inhalers varies. Ease of use is seen as an important consideration when selecting an inhaler device, which should be evaluated in real-life studies using unselected patient populations. In conclusion, the evidence suggests that patients cannot use all dry powder inhalers equally well.

Do patients show the same level of adherence with all dry powder inhalers?

Poor adherence with inhaled therapy presents a considerable problem. In the UK, non-adherence is estimated to occur in 10-46% of those prescribed inhaled corticosteroids and may contribute to an estimated 18-48% of asthma deaths. Before dry powder inhalers can be considered interchangeable, it is important to check that adherence is unaffected by any switching of the device dispensed to patients. Numerous studies have shown that adherence with inhaled medication is a multifactorial issue. A number of evidence-based guidelines have concluded that there is no difference in the delivery of treatments from different inhaler devices. However, many studies comparing different devices are designed to show equivalence. It is therefore difficult to determine whether the studies on which the guidelines are based were conducted with treatments already being used at the top of a dose-response curve. Furthermore, studies use selected patient populations who consent to take part and consequently receive regular contact with healthcare professionals, with emphasis on using the correct inhaler technique and on compliance. These studies do not therefore necessarily reflect real life. It is possible that patient preferences or perceptions of differences in efficacy are behind complaints when devices are switched. Patients vary in their preference for different dry powder inhalers, as shown in numerous studies of patient attitudes. There is evidence to indicate that patient claims of differences between inhalers that contain the same molecule from different manufacturers may have an objective basis. Healthcare professionals increasingly recognise the impact of patient attitudes on adherence. Accepting that patients make choices about their therapy is an integral part of achieving the partnership in management recommended by guidelines. The most effective treatment will not achieve disease control if it is not used or if it is used incorrectly. It may be short-sighted to change a device that a patient has chosen to one that is just given without consent, as this may result in poor adherence to therapy with consequent loss of control.

The relationship between the quality of prescribing and practice appointment rates with asthma management data in those admitted to hospital due to an acute exacerbation.

Specific targeting of patients with a previous asthma hospitalisation could be more focused if predictors could be identified. This study was an observational retrospective analysis using ridge and linear multivariate regression analysis. Patient asthma management data were extracted from the hospital and general practice notes of those that had been admitted with an acute exacerbation of their asthma over a 5-year period. From the prescribing data, the annual doses of preventer (P) and reliever (R) medication were converted to defined daily doses then divided to give a P:R ratio. Preliminary statistical analysis was used to identify any association between either the P:R ratio or for the number of general practitioner (GP) practice appointments (PA) and their asthma management data. Multivariate regression analysis was applied to the P:R ratio and to PA to determine a model between each of these and asthma management data/events. GPs gave consent to access the data of 115 (out of 440) asthmatics, age >5 years, admitted to a district general hospital for asthma exacerbations between 1994 and 1998. The multivariate analysis revealed that PA was associated with oral prednisolone rescue courses (PRCs) and age whilst the P:R ratio was associated to PRCs and more reliever usage but not preventers. Patients with low preventer usage with respect to their reliever medication should be targeted for medication review as these were the patients prescribed more prednisolone courses and their increased PAs reflect this. This could decrease visits to the doctor and acute exacerbations.

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

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

In-vitro intra- and inter-inhaler flow rate-dependent dosage emission from a combination of budesonide and eformoterol in a dry powder inhaler.

Some dry powder inhalers have profound inhalation flow rate-dependent dosage emission, and it has been suggested that there are links between the in vitro emitted dose, total lung deposition, and subsequent clinical response. We have measured the in vitro dosage delivery for a combination of budesonide and eformoterol in a new version of the Turbuhaler. At inhalation flow rates of 30, 60, and 90 Lmin(-1), the total dose emission for 10 separate inhalations from each of six inhalers was determined. The aerodynamic characteristics of the emitted dose using inhalation flow rates of 28.3 and 60 Lmin(-1) were measured using the Andersen Cascade Impactor. The mean (SD) emitted dose for budesonide, at 30, 60, and 90 Lmin(-1), was 37.5%(18.2%), 64.4%(16.6%), and 107.4%(36.0%) (of the nominal emitted dose), respectively, and for eformoterol were 38.0%(20.3%), 65.0%(16.8%), and 104.9%(36.2%) (of the nominal emitted dose), respectively. Variability of dose emission characteristics from each inhaler and between inhalers at each flow rate was found. The aerodynamic particle size characterization of the emitted dose at flow rates of 28.3 and 60 Lmin(-1) revealed a mean fine particle dose for budesonide of 11.9% and 28.6% of the nominal emitted dose, respectively, and similarly 10.0% and 26.3% for eformoterol. At 28.3 Lmin(-1), the majority of the emitted dose (54.8% for budesonide and 64.5% for eformoterol) was deposited in the throat and preseparator of the Andersen Cascade Impactor. The mass median aerodynamic diameters for budesonide and eformoterol at 28.3 Lmin(-1) were 3.2 and 3.6 microm, respectively, and similarly at 60 Lmin(-1) were 2.4 and 2.5 microm. The modified Turbuhaler containing a budesonide and eformoterol combined formulation shows intra- and inter-inhaler flow-dependent dosage emission. The clinical significance of the in vitro dose-dependent properties should be investigated.

A Cox regression analysis of covariates for asthma hospital readmissions.

BACKGROUND: Asthma hospital admissions and readmissions are unacceptably high, thus, a method to identify those at greatest risk could be helpful. METHODS: An observational retrospective study using a Cox regression to determine the relationship between the time interval between admissions and possible covariates of a readmission. The covariates were age, sex, ethnicity, smoking habit, history of allergy or eczema/hay fever, age of onset, Townsend index (TI), Jarman score (JS), and drugs on discharge. Those with p < 0.2, together with interacting covariates, from the preliminary analysis were eligible for the multivariate Cox regression analysis. RESULTS: Of the 523 patients admitted between 1994 and 1998 because of their asthma, complete data were available for 440. Of these, 112 were readmitted. Eligible covariates for the multivariate Cox regression analysis were sex, allergy status, history of eczema/hay fever, the JS and TI together with interactions between JS and TI, JS and allergy, and allergy with eczema/hay fever. There were 278 subjects (71 with a readmission) with complete data for these eligible covariates. The multivariate analysis revealed that female sex (odds ratio [OR] = 2.65, 95% confidence interval [CI] 1.42, 4.92), high JS (OR = 2.03, 95% CI 1.13-3.65), and history of allergy (OR = 1.88, 95% CI 1.06-3.32) formed the final model as significant predictors of readmission. CONCLUSION: Females with a history of allergy that were registered at a practice with a high workload (JS) had a higher risk of readmission. The analysis method used highlights how those at risk of readmission can be identified so that they can be targeted post discharge.