The preclinical toxicology of salmeterol hydroxynaphthoate

Abstract

<jats:p> An extensive toxicology programme on salmeterol hydroxynaphthoate (Serevent<jats:sup>TM</jats:sup>), a marketed long-acting β<jats:sub>2</jats:sub>-adrenoceptor agonist, has been carried out. The studies evaluated both the local (respiratory tract) and systemic tolerance to single and repeated dosing, effects on all stages of reproduction, as well as the genotoxic and oncogenic potential. High acute doses were well tolerated and caused no specific target organ toxicity. In repeat dose studies, animals tolerated salmeterol very well both locally and systemically. No significant effects on the respiratory tract of dogs were seen and only minor laryngeal changes, typical of those occurring with many inhaled medicines, were noted in rats. The high systemic concentrations achieved resulted in a number of changes that are considered to be the result of excessive and prolonged β<jats:sub> 2</jats:sub>-adrenoceptor stimulation. These included tachycardia, skeletal muscle hypertrophy and minor haematological and blood biochemical changes in general toxicity studies, foetal effects in rabbit organogenesis studies and increased incidences of smooth muscle tumours of the mesovarium in the rat and of the uterus in the mouse oncogenicity studies. Salmeterol showed no evidence of any genotoxic potential. Results of the extensive toxicology programme provide good assurance of the safety for the inhaled use of salmeterol in patients; this has ben confirmed by many years of clinical experience during its development and marketing. </jats:p>

Foamy macrophage responses in the rat lung following exposure to inhaled pharmaceuticals: a simple, pragmatic approach for inhaled drug development

“…β 2 -Agonists. Foamy macrophage responses seen in rats exposed to β 2 -agonists (Owen et al, 2010) may be explained by the presence of β 2 -adrenergic receptors on ATII cells and consequent increased surfactant synthesis and its subsequent phagocytosis (Chander and Fisher, 1990;Mason and Voelker, 1998;Rooney, 2001). Corticosteroids have been shown to upregulate these receptors (Mason and Voelker, 1998;Salonen and Matilla, 1984).…”

Effects of Salmeterol on Skeletal Muscle Cells

“…The extensive animal-based research makes it clear that the administration of ß-agonists (especially in high doses) can produce significant undesirable physiological adverse effects that are likely to deleteriously affect athletic performance in the long term. The most frequently adverse effects associated with the use of salmeterol include nausea, headaehes, muselé tremor, palpitation, muscle eramp, peripheral vasodilatation, tachycardia, and myocardial infarction (29). Moreover, it has been demonstrated that the ß2-AR agonist elenbuterol is capable of inducing myocyte apoptosis (3).…”