I Oulette JJ, Reed CE. Increased response of asthmatic subjects to methacholine after influenza vaccine. JAllergy 1%5;36:558-63. 2 Bachmayer H. Selective solubilisation of haemagglutinin and neuraminidase from influenza viruses. Intervirology 1975;5:260-S8. 3 Barry DW, Mayner RE, Hockstein HD, et al. Comparative trial of influenza vaccines. II. Adverse reactions in children and adults. AmJ Epidemiol 1976;104:47-59. 4 Cockcroft DW, Killian DN, Mellon nJ, Hargreave FE. Bronchial reactivity to inhaled histamine: a method and clinical survey. Clin Allerk 1977;7:235-43. 5 Grilli EA, Smith AJ. The use of a radial haemolysis test for neuraminidase antibodies in the diagnosis of influenza A infection. J Hyg (Camb) 1983;91:147-56.

https://www.bmj.com/content/bmj/294/6581/1197.2.full.pdf

Bronchoconstrictor properties of preservatives in ipratropium bromide (Atrovent) nebuliser solution.

1. The chemosensitivity of cough receptors stimulated by inhalation of aqueous aerosols was evaluated in 21 normal volunteers in three experiments. 2. The pH of isotonic saline was altered using small amounts of phosphate or glycine buffers to produce solutions with a pH range of 2.6–10.0. These solutions were nebulized ultrasonically and breathed for 1 min periods by seven subjects in random order and on separate days. Cough frequency during each 1 min inhalation was recorded. Only the two solutions of extreme pH (2.6 and 10.0) caused cough. 3. The effect of altering the osmolarity of the inhaled aerosol on cough was assessed using d-glucose over a range of 77–1232 mosmol/l. Saline solutions over the same range of osmolarity were also tested. The pH of d-glucose was raised to match that of saline by adding small amounts of sodium hydroxide. All solutions were nebulized and inhaled by seven subjects as described above for 1 min periods during which cough frequency was recorded. Forced expired volume in 1 s was recorded after each inhalation and did not alter in any subject by more than 10%. Subjects coughed when inhaling all the d-glucose solutions over the whole range of osmolarity. Cough occurred with saline solutions only at low chloride concentration and at the highest concentration. 4. In order to clarify whether the response to hypertonic saline was due to the high ionic content of the solutions or to its hypertonicity, two other solutions were tested. These were an isotonic and a hypertonic mixture of d-glucose and saline, containing ‘normal’ (150 mmol/l) ionic content. Cough occurred with the hypertonic solution but not with the isotonic solution, suggesting that hypertonicity does stimulate cough. 5. The mechanism of cough induction by citric acid was studied. An aerosol of 0.68% citric acid in saline was compared with sodium citrate, both with and without chloride, with d-glucose and with water in seven subjects. Cough occurred in response to all aerosols except sodium citrate in saline solvent. Additive effects of low pH and lack of chloride, and not the citrate ion, are responsible for the irritant properties of citric acid. 6. The chemosensitivity of the cough reflex induced by inhaled aerosols mirrors that already described in vivo for laryngeal rapidly adapting receptors.

Effects of pH and osmolarity on aerosol-induced cough in normal volunteers.

/pdf/adverse-reactions-to-the-non-drug-constituents-of-nebuliser-4388c5vfn5.pdf

Adverse reactions to the non-drug constituents of nebuliser 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 μg BAC/dose, which is below the threshold for bronchoconstriction whereas the screwcap unit-dose vial contains 300 μg/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 μg 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 μg 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. (J Allergy Clin Immunol 1999;104:S53-60.)

https://www.jacionline.org/article/S0091-6749(99)70274-5/pdf

Bronchoconstrictor additives in bronchodilator solutions

Learning Objectives To review the rationale supporting the use of levalbuterol [(R)-albuterol] for the treatment of pediatric and adult asthma. Data Sources Peer-reviewed articles, selected abstracts from studies presented at recent professional meetings, and the Xopenex [levalbuterol, (R)-albuterol; Sepracor, Marlborough, MA] Summary Basis of Approval and package insert. Study Selection Institutional review board-approved clinical study protocols. Results Levalbuterol is a single isomer β 2 -agonist that differs from racemic albuterol by elimination of (S)-albuterol. Levalbuterol is an effective bronchodilator whose primary mechanism of action is unimpeded by (S)-albuterol. Thus, when compared with racemic albuterol, clinically comparable bronchodilation can be achieved with doses that substantially lessen β-mediated side effects. In chronic or acute treatment of asthma, this favorable therapeutic profile cannot apparently be duplicated by increasing or decreasing the dose of racemic albuterol or by the addition of anticholinergic agents such as ipratropium bromide. Conclusions Levalbuterol seems to provide efficacy and safety advantages in pediatric and adult patients suffering from asthma. Its use may afford a cost benefit as well. More clinical studies are required to extend these observations for use in the treatment of other pulmonary diseases in both adults and children and to determine levalbuterol's impact on long-term therapy of respiratory diseases.

Levalbuterol; pharmacologic properties and use in the treatment of pediatric and adult asthma

In previous studies, a 5-min inhalational challenge with 10% citric acid aerosol (0.52 M) elicited bronchoconstriction in Basenji-Greyhound (BG) dogs with hyperreactive airways but not in mongrel dogs. This response was independent of vagal reflexes because it was not attenuated by atropine. Citric acid might elicit bronchoconstriction because of acidity, calcium chelation, or some other effect of the citrate molecule. To assess these factors, barbiturate-anesthetized BG dogs were challenged (5 min) with aerosols of 10% acetic acid or a citric acid (0.48 M)/Na3citrate (0.04 M) mixture of equivalent pH, 6% Na2-ethylenediaminetetraacetic acid (EDTA), or 6% CaNa2EDTA. Each challenge was delivered in a separate week. The acidity alone was not an adequate stimulus, since pulmonary resistance (RL) was unaltered by 10% acetic acid, although markedly increased by the citric acid-Na3citrate mixture [2.2 +/- 0.4 (SE) cmH2O X l-1 X s prechallenge, 10.0 +/- 2.2 postchallenge]. Aerosols of Na2EDTA provoked a similar increase in RL (2.1 +/- 0.4 cmH2O X l-1 X s prechallenge, 9.0 +/- 1.8 postchallenge). Neither effect was attenuated by intravenous atropine (0.2 mg/kg). CaNa2EDTA caused no changes in RL. We conclude that it is the calcium chelating action of citric acid rather than its acidity that is responsible for bronchoconstriction in BG dogs with hyperreactive airways.

H. Downes

Papers

Importance of calcium in citric acid-induced airway constriction.