Comparison of the anti-bronchoconstrictor activities of inhaled formoterol, its (R,R)- and (S,S)-enantiomers and salmeterol in the rhesus monkey.
The principle objective of this study was to define the anti-bronchoconstrictor effects of inhaled racemic formoterol and its (R,R)- and (S,S)-enantiomers in a new model of methacholine-induced bronchoconstriction in the rhesus monkey. A second long-acting beta(2)agonist, salmeterol, was included for comparison. Anaesthetized, spontaneously breathing rhesus monkeys were set up for measuring airway resistance. Blood pressure, heart rate and serum potassium concentrations were measured concomitantly to gauge systemic exposure and the potential for side effects. Formoterol, 0.14, 0.34 and 1.15 microg/kg, administered by aerosol, induced rapidly developing, sustained, dose-related inhibition of the bronchoconstrictor responses to aerosolised methacholine (maximum 76%) accompanied by sustained, dose-related tachycardia. (R,R)-formoterol, 0.56 microg/kg, induced anti-bronconstrictor effects and an associated tachycardia which corresponded closely to the effects seen following twice the dose of the racemate. (S,S)-formoterol, 0.54 microg/kg, was inactive. Salmeterol, 1.4 microg/kg, had no significant anti-bronchoconstrictor effect whereas doses of 5.5 and 30 microg/kg produced quantitatively similar but submaximal anti-bronchoconstrictor effects (maximum 47%). Sustained dose-dependent tachycardia was seen with salmeterol over the full dose range. Thus, the anti-bronchoconstrictor activity of formoterol resides in the (R,R) enantiomer and the (S,S) enantiomer does not interfere with the activity when present in the racemic form. Furthermore, the data indicate that the present model of methacholine-induced bronchospasm in the rhesus monkey could be useful in defining the key properties of beta(2)agonist bronchodilators such as relative potency, efficacy, duration of action and potential for systemic side effects.
Fozard
J R
JR
Research Department, Novartis Pharma AG, CH-4002 Basel, Switzerland. john.r.fozard@pharma.novartis.com
Buescher
H
H
D000280:Administration, Inhalation; D000403:Airway Resistance / Q000187:drug effects*; D000420:Albuterol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D001986:Bronchial Spasm / Q000139:chemically induced / Q000188:drug therapy; D016085:Bronchoconstrictor Agents / Q000037:antagonists & inhibitors; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004983:Ethanolamines / Q000008:administration & dosage / Q000494:pharmacology*; D000068759:Formoterol Fumarate; D008253:Macaca mulatta; D008297:Male; D016210:Methacholine Chloride / Q000008:administration & dosage / Q000009:adverse effects; D000068299:Salmeterol Xinafoate; D013610:Tachycardia / Q000139:chemically induced
D016085:Bronchoconstrictor Agents; D001993:Bronchodilator Agents; D004983:Ethanolamines; D016210:Methacholine Chloride; D000068299:Salmeterol Xinafoate; D000420:Albuterol; D000068759:Formoterol Fumarate