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-α 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.

Keywords:
Cat, R-Albuterol, S-Albuterol, Inhalation
1.
Cherry D, Burt C, Woodwell D: National ambulatory medical care survey: 2001 Summary. Adv Data 2003;337:1–44.
2.
D’Alonzo G: Levalbuterol in the treatment of patients with asthma and chronic obstructive lung disease. JAOA 2004;104:288–293.
3.
Cho S, Hartleroad J, Oh C: (S)-Albuterol increases the production of histamine and IL-4 in mast cells. Int Arch Allergy Immunol 2001;124:478–484.
4.
Baramki D, Koester J, Anderson A, Borish L: Modulation of T-cell function by (R)- and (S)-isomers of albuterol: anti-inflammatory influences of (R)-isomers are negated in the presence of the (S)-isomer. J Allergy Clin Immunol 2002;109:449–454.
5.
Agrawal DK, Ariyarathna K, Kelbe P: (S)-Albuterol activates pro-constrictory and pro-inflammatory pathways in human bronchial smooth muscle cells. J Allergy Clin Immunol 2004;113:503–510.
6.
Mitra S, Ugur M, Ugur O, Goodman H, McCullough J, Yamaguchi H: (S)-Albuterol increases intracellular free calcium by muscarinic receptor activation and a phospholipase C-dependent mechanism in airway smooth muscle. Mol Pharmacol 1998;53:347–354.
7.
Volcheck G, Kelkar P, Bartemes K, Gleich G, Kita H: Effects of (R)- and (S)-isomers of β-adrenergic agonists on eosinophil response to interleukin-5. Clin Exp Allergy 2005;35:1341–1346.
8.
Henderson W, Banerjee E, Chi E: Differential effects of (S)- and (R)-enantiomers of albuterol in a mouse asthma model. J Allergy Clin Immunol 2005;116:332–340.
9.
Eaton E, Walle U, Wilson H, Aberg G, Walle T: Stereoselective sulphate conjugation of salbutamol by human lung and bronchial epithelial cells. Br J Clin Pharmacol 1996;41:201–206.
10.
Dhand R, Goode M, Reid R, Fink J, Fahey P, Tobin M: Preferential pulmonary retention of (S)-albuterol after inhalation of racemic albuterol. Am J Repir Crit Care Med 1999;160:1136–1141.
11.
Canning B: Modeling asthma and COPD in animals: a pointless exercise? Curr Opin Pharmacol 2003;3:244–250.
12.
Barnes P: Treatment with (R)-albuterol has no advantage over racemic albuterol. Am J Resp Crit Care Med 2006;174:969–972.
13.
Qureshi F, Zaritsky A, Welch C, Meadows T, Burke B: Clinical efficacy of racemic albuterol versus levalbuterol for the treatment of acute pediatric asthma. Ann Emerg Med 2005;46:29–36.
14.
Sjöswärd K, Hmani M, Davidsson A, Söderkvist P, Schmekel B: Single-isomer R-salbutamol is not superior to racemate regarding protection for bronchial hyperresponsiveness. Respir Med 2004;98:990–999.
15.
Hardasmalani M, DeBari V, Bithoney W, Gold N: Levalbuterol versus racemic albuterol in the treatment of acute exacerbation of asthma in children. Pediatr Emerg Care 2005;21:415–419.
16.
Moise N, Wiedenkeller D, Yeager A: Clinical, radiographic, and bronchial cytologic features of cats with bronchial disease: 65 cases (1980–1986). J Am Vet Med Assoc 1989;194:1467–1473.
17.
Howard E, Ryan C: Chronic obstructive pulmonary disease in the domestic cat. Calif Vet 1982;6:7–11.
18.
Dye J, McKiernan B, Rozanski E, Hoffmann W: Bronchopulmonary disease in the cat: historical, physical, radiographic, clinicopathologic, and pulmonary functional evaluation of 24 affected and 15 healthy cats. J Vet Intern Med 1996;10:385–400.
19.
Norris Reinero C, Decile K, Berghaus R, Williams K, Leutenegger C, Walby W, Schelegle E, Hyde D, Gershwin L: An experimental model of allergic asthma in cats sensitized to house dust mite or Bermuda grass allergen. Int Arch Allergy Immunol 2004;135:117–131.
20.
Dhand R, Berghaus R, Gershwin L, Reinero C: Does nebulized racemic albuterol provoke airway inflammation in cats? Proc Am Thoracic Soc 2005;2:A357.
21.
Waldrep J, Berlinski A, Dhand R: Comparative analysis of methods to measure aerosols generated by a vibrating mesh nebulizer. J Aerosol Med 2007;20:310–319.
22.
Reinero C, Cohn L, Delgado C, Spinka C, Schooley E, DeClue A: Adjuvanted rush immunotherapy using CpG oligodeoxynucleotides in experimental feline allergic asthma. Vet Immunol Immunopath 2008;121:241–250.
23.
Westerhof F, Zuidhof A, Kok L, Meurs H, Zaagsma J: Effects of salbutamol and enantiomers on allergen-induced asthmatic reactions and airway hyperreactivity. Eur Respir J 2005;25:864–872.
24.
Frohock J, Wijkstrom-Frei C, Salathe M: Effects of albuterol enantiomers on ciliary beat frequency in ovine tracheal epithelial cells. J Appl Physiol 2002;92:2396–2402.
25.
Ibe B, Portugal A, Raj J: Levalbuterol inhibits human airway smooth muscle cell proliferation: therapeutic implications in the management of asthma. Int Arch Allergy Immunol 2006;139:225–236.
26.
Jalba MS: Three generations of ongoing controversies concerning the use of short acting beta-agonist therapy in asthma. J Asthma 2008;45:9–18.
27.
Gumbhir-Shah K, Kellerman D, DeGraw S, Koch P, Jusko W: Pharmacokinetic and pharmacodynamic characteristics and safety of inhaled albuterol enantiomers in healthy volunteers. J Clin Pharmacol 1998;38:1096–1106.
28.
Schmekel B, Rydberg I, Norlander B, Sjöswärd K, Ahlner J, Andersson R: Stereoselective pharmacokinetics of S-salbutamol after administration of racemate in healthy volunteers. Eur Respir J 1999;13:1230–1235.
29.
Ward J, Dow J, Dallow N, Enynott P, Milleri S, Ventresca G: Enantiomeric disposition of inhaled, intravenous and oral racemic-salbutamol in man – no evidence of enantioselective lung metabolism. Br J Clin Pharmacol 2000;49:15–22.
30.
Lipworth B, Clark D, Koch P, Arbeeny C: Pharmacokinetics and extrapulmonary β2-adrenoceptor activity of nebulised racemic salbutamol and its R and S isomers in healthy volunteers. Thorax 1997;52:849–52.
31.
Jacobson G, Chong F, Baker R: (R,S)-Salbutamol plasma concentrations in severe asthma. J Clin Pharm Ther 2003;28:235–238.
32.
Gauvreau G, Jordana M, Watson R, Cockcroft D, O’Byrne P: Effect of regular inhaled albuterol on allergen-induced late responses and sputum eosinophils in asthmatic subjects. Am J Respir Crit Care Med 1997;156:1738–1745.
33.
Swystun V, Gordon J, Davis B, Zhang X, Cockcroft D: Mast cell tryptase release and asthmatic responses to allergen increase with regular use of salbutamol. J Allergy Clin Immunol 2000;106:57–64.
34.
Gordon J, Swystun V, Li F, Zhang X, Davis B, Hull P, Cockcroft D: Regular salbutamol use increases CXCL8 responses in asthma: relationship to the eosinophil response. Eur Respir J 2003;22:118–126.
35.
Cockcroft D, Swystun V: Effect of single doses of S-salbutamol, R-salbutamol, recemic salbutamol, and placebo on the airway response to methacholine. Thorax 1997;52:845–848.
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2009
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