title: Cardiovascular effects after inhalation of large doses of albuterol dry powder in rats, monkeys, and dogs: a species comparison.
abstract: Albuterol is a quickly acting beta-2 adrenergic agonist bronchodilator widely used by asthmatics. Because recent case-control studies have suggested a relationship between the increase in mortality of asthmatics over the past decade and the use of beta 2-adrenergic agonists in the control of asthma, concern has developed regarding the potential cardiotoxicity of beta 2-specific adrenergic agonists, including albuterol. The aim of this investigation was to assess the potential for cardiotoxicity of inhaled albuterol dry powder in rats, monkeys, and dogs. All species were exposed to an aerosol of albuterol 1 h per day, 7 days per week, for at least 2 weeks. Control groups were exposed to filtered conditioned air and handled in the same manner as the albuterol-exposed animals. Plasma concentrations of albuterol confirmed systemic exposure. The daily inhaled dose received by the animals was calculated based on measured respiratory minute volumes, published respiratory tract deposition data, as well as HPLC-determined particle size distribution data and aerosolized albuterol concentrations. Multiples of the maximum daily clinical dose (presentation of 15 micrograms/kg in a 70-kg human) were approximately 0.25- to 2500-fold in the rat, 9- to 100-fold in the monkey, and 0.5- to 90-fold in the dog. No findings attributed to albuterol were observed in the monkey. Tachycardia and transient hypokalemia occurred in rats at multiples of 1.5 times or greater of the maximum clinical dose. Absolute and relative heart weights increased in rats receiving multiples of 47 times or greater of the maximum human dose. In the absence of histopathologic findings, the increases in rat heart weights were considered a physiologic hypertrophic response to tachycardia. In dogs tachycardia and transient hypokalemia occurred at all doses tested. Slight to mild fibrosis in the papillary muscles of the left ventricle of the heart occurred in dogs at multiples > or = 19 times the clinical dose. The cardiovascular effects observed were consistent with the known pharmacologic action of beta 2-adrenergic agonists. Due to the lack of toxicologically relevant findings in rats and monkeys and the wide safety margin in dogs, the findings in this study do not suggest a cardiotoxicity risk in the human population after repeated exposures to clinical doses of albuterol currently used in the treatment of asthma.
authors.affiliation: Schering-Plough Research Institute, Lafayette, New Jersey 07848, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Petruska
authors.forename: J G
authors.initials: JG
authors.lastname: Beattie
authors.forename: B O
authors.initials: BO
authors.lastname: Stuart
authors.forename: S
authors.initials: S
authors.lastname: Pai
authors.forename: K M
authors.initials: KM
authors.lastname: Walters
authors.forename: C M
authors.initials: CM
authors.lastname: Banks
authors.forename: G W
authors.initials: GW
authors.lastname: Lulham
authors.forename: E J
authors.initials: EJ
authors.lastname: Mirro
mesh_terms: D000280:Administration, Inhalation; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D000420:Albuterol / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D008176:Lung Volume Measurements; D008252:Macaca fascicularis; D009206:Myocardium / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D010316:Particle Size; D011188:Potassium / Q000097:blood; D011208:Powders; D051381:Rats; D017207:Rats, Sprague-Dawley; D012129:Respiratory Function Tests; D013045:Species Specificity
chemical_list: D000318:Adrenergic beta-Agonists; D011208:Powders; D000420:Albuterol; D011188:Potassium