Michael J. Asmus

Levalbuterol Nebulizer Solution: Is It Worth Five Times the Cost of Albuterol?

Albuterol is a 50:50 mixture of R‐albuterol, the active enantiomer, and S‐albuterol, which appears to be inactive in humans. The Food and Drug Administration recently approved levalbuterol, the pure R‐isomer, as a preservative‐free nebulizer solution. Published studies indicate that it is neither safer nor more effective than an equimolar dose of racemic albuterol (levalbuterol 1.25 mg = albuterol 2.5 mg). However, these studies were conducted in patients with stable asthma (at the top of the dose‐response curve), whereas a nebulized bronchodilator most likely would be used by patients with an acute exacerbation. Because such patients, in the hospital setting, often require higher doses of albuterol, the manufacturers recommended dose of levalbuterol is likely to be too low for rescue therapy. Levalbuterol may cost as much as 5 times more than racemic albuterol, depending on purchase method. We conclude that levalbuterol offers no advantage over albuterol but is likely to be more costly.

Bronchoconstrictor additives in bronchodilator solutions

Nebulized bronchodilator solutions are available in the United States as both nonsterile and sterile-filled products. Sulfites, benzalkonium chloride (BAC), or chlorobutanol are added to nonsterile products to prevent bacterial growth, but there have been reports of contaminated solutions containing preservatives. Ethylenediamine tetraacetic acid (EDTA) is added to some products to prevent discoloration of the solution. With the exception of chlorobutanol, all of these additives are capable of inducing bronchospasm in a concentration-dependent manner. However, it is rarely apparent to the patient or health care provider that the additive diminishes the bronchodilator effects. Older products (eg, isoproterenol and isoetharine) contain enough sulfites to produce bronchospasm in most patients with asthma, even in those without a prior history of sulfite sensitivity. Bronchoconstriction from inhaled BAC is cumulative, prolonged, and correlates directly with basal airway responsiveness. The multidose dropper bottle of albuterol contains 50 microg BAC/dose, which is below the threshold for bronchoconstriction whereas the screwcap unit-dose vial contains 300 microg/dose, which is above the threshold for many patients. If the screwcap product is used in the emergency department, a patient could receive as much as 1800 microg of BAC in the first hour. Three sterile-filled unit dose albuterol products contain no additives, whereas a fourth, (manufactured by Dey Laboratories) contains 300 microg of EDTA, which is also below the threshold dose for bronchoconstriction. Only additive-free sterile solutions should be used for hourly or continuous nebulization of albuterol. The multidose dropper bottle or the Dey product can be used when the interval between doses is longer, whereas the screwcap product should not be used for acute therapy. Ipratropium is available only as a sterile, additive-free unit-dose vial, as is levalbuterol.

In Vitro Performance of Two Common Valved Holding Chambers with a Chlorofluorocarbon‐Free Beclomethasone Metered‐Dose Inhaler

Study Objective. To compare in vitro aerosol deposition from a beclomethasone dipropionate metered‐dose inhaler (MDI) containing hydrofluoroalkane propellant with that of the MDI in combination with two common valved holding chambers (VHCs) to evaluate how these VHCs affect the respirable dose of beclomethasone dipropionate.

Evaluation of cytokine modulators for asthma

Th2 cytokines play an important role in producing and maintaining airway inflammation in asthma. As a consequence, there is considerable interest in developing agents that modulate their effects. Therapeutic strategies include decreasing cytokine synthesis or release, blocking their effects by antibodies or soluble receptors, as well as administration of anti-inflammatory cytokines. Initial studies of three of these approaches have shown interesting results. The first is suplatast tosilate, a selective Th2-inhibitor that suppresses the synthesis of IL-4 and IL-5 in vitro. In a randomised double-blind placebo-controlled parallel study, suplatast, given orally TID, improved lung function and symptom control when added to inhaled beclomethasone for 4 weeks and prevented deterioration when the beclomethasone dose was decreased by 50% during a second 4 weeks. The second is CDP840, a second generation phosphodiesterase type 4 inhibitor, that may decrease the release of cytokines from eosinophils and Th2 lymphocytes. In a double-blind placebo-controlled crossover study, CDP840, given orally BID for 9 days, attenuated the late response to allergen by 30% when compared to placebo. The third is a recombinant human soluble IL-4 receptor (altrakincept) that neutralises endogenously produced IL-4. In inhaled steroid-dependent subjects, weekly nebulisation of altrakincept prevented lung function decline and asthma exacerbations after abrupt withdrawal of inhaled corticosteroids. In contrast, studies of anti-IL-5 monoclonal antibodies (mepolizumab and SCH55700) indicate that this strategy only partially depletes eosinophils from the bronchial mucosa and shows no benefit on clinical markers of asthma activity. Of these novel therapeutic approaches, inhibiting Th2 synthesis of IL-4 and IL-5 (suplatast) appears to offer the greatest potential and long-term studies of this approach should be undertaken.

In Vitro Performance Characteristics of Valved Holding Chamber and Spacer Devices with a Fluticasone Metered-Dose Inhaler

Study Objective. To compare the in vitro aerosol deposition characteristics of several commercially available valved holding chamber (VHC) and spacer devices used with a fluticasone metered‐dose inhaler (MDI).

A 500-ml plastic bottle: an effective spacer for children with asthma.

Inhaled therapy using a metered‐dose inhaler (MDI) with attached spacer has been increasingly recognized as the optimal method for delivering asthma medication for acute attacks and chronic prophylaxis. However, in developing countries the cost and availability of commercially produced spacers limit the use of MDI‐spacer delivery systems. A 500‐ml plastic bottle has been recently adapted to function as a spacer. This article reviews the current data on the efficacy of this bottle‐spacer and discusses its advantages and limitations. It is concluded that a modified 500‐ml plastic bottle is an effective spacer; modification and use of this device should be incorporated into international guidelines for the management of children with asthma.

In vitro deposition of fluticasone aerosol from a metered-dose inhaler with and without two common valved holding chambers

BACKGROUND Previous in vitro aerosol deposition experiments indicate that the corticosteroid respirable dose from a metered-dose inhaler (MDI) can vary by threefold depending on the specific valved holding chamber (VHC) MDI combination. OBJECTIVE We compared in vitro aerosol deposition from a fluticasone propionate MDI (Flovent, GlaxoSmithKline, Research Triangle Park, NC) to that of the same MDI used in combination with two VHCs (EasiVent, Dey, Napa, Ca; and AeroChamber-Plus, Monaghan Medical Corp, Plattsburgh, NY) to evaluate how these VHCs affect the respirable dose of fluticasone. METHODS The respirable dose (aerosol particles 1 to 5 microm in size) of fluticasone was determined by sampling 5 x 110-microg actuations from each configuration (MDI alone, MDI plus AeroChamber-Plus, and MDI plus EasiVent) in multiples of ten using a well established, in vitro cascade impactor method. Fluticasone aerosol was washed from individual impactor stages with 50% methanol and quantified via ultraviolet high-pressure liquid chromatography. Differences among outcomes were determined using analysis of variance. RESULTS Mean respirable dose from AeroChamber-Plus (47.9 +/- 6.9 microg/actuation) was not different (P > 0.05) from that produced by the MDI alone (50.3 +/- 2.2 microg/actuation). EasiVent respirable dose (27.0 +/- 3.6 microg/actuation) was less than that produced by either the AeroChamber-Plus or the MDI alone (P < 0.001). CONCLUSIONS VHCs do not display equivalent in vitro performance with a fluticasone MDI. If a patient needs a VHC, clinicians should use available in vitro performance information to aid in selecting the best device.

Tobramycin as a pharmacologic tracer to compare airway deposition from nebulizers.

Study Objective. To assess the utility of inhaled tobramycin as a pharmacologic tracer for comparing lung deposition from a prototypic breath‐actuated jet nebulizer connected to an electronic pressure sensor designed to coordinate nebulization with inspiration with that from a continuously operating standard jet nebulizer.

In Vitro Characteristics of Tobramycin Aerosol from Ultrasonic and Jet Nebulizers

Study Objective. To compare the in vitro performance of an ultrasonic nebulizer and a jet nebulizer in producing a respirable aerosol of tobramycin solution for injection.

Performance of a Corticosteroid Inhaler with a Spacer Fashioned from a Plastic Cold-Drink Bottle: Effects of Changing Bottle Volume

Some clinicians advocate using metered-dose inhaler (MDI) spacers prepared from common household bottles. We evaluated the in vitro aerosol characteristics of fluticasone from the MDI alone and through spacers fashioned from 237-, 500-, 1000-, and 1500-mL polyethylene terephlate plastic cold drink bottles using a cascade impactor. Ten 110-µg actuations of fluticasone were sampled into the impactor during each of five runs with each configuration. The primary outcomes were the respirable dose (i.e., quantity aerosol 1.1–4.7 µm in size) and the quantity trapped in the oropharynx. The mean fluticasone respirable dose from the MDI alone (46.2 µg/actuation) was no different (p>0.05) compared with the same MDI mated to any of the bottle spacers, regardless of volume. The mean quantity of fluticasone trapped in the oropharynx from the MDI alone (39.2 µg /actuation) was greater (p < 0.001) than the same MDI mated with any bottle spacer (range 1.5–3.5 µg/actuation). These data suggest that any of the bottle spacers tested would be an acceptable method to decrease the quantity of fluticasone that would deposit onto the oropharynx and thereby diminish the risk of topical adverse effects. Among the range of volumes tested, there was no relationship between spacer volume and respirable dose of fluticasone.