Is beta-adrenergic-mediated airway relaxation of salmeterol antagonized by its solvent xinafoic acid?
OBJECTIVE
Isolated case reports of asthmatic fatalities accompanied by the use of salmeterol have raised the question whether a paradoxical effect of salmeterol or its vehicle on the airways might contribute to these fatalities. We questioned whether salmeterol's solvent, xinafoic acid, has detrimental effects on the tone of airways or on beta-adrenoceptor binding.


METHODS
Basenji-greyhound dogs were anesthetized and their peripheral airways challenged with xinafoic acid via a wedged bronchoscope technique. Radioligand binding assays were performed in lung membranes prepared from these dogs.


RESULTS
In contrast to a methacholine control, xinafoic acid (0.001 to 1.0 mg/mL) aerosolized into the peripheral airways of anesthetized dogs did not increase airway resistance. Xinafoate alone had no significant effect on the specific binding of 125I-cyanopindolol to lung membranes and did not affect the affinity of salmeterol for the beta-adrenoceptor in the absence or presence of xinafoate, respectively (-log concentration that inhibits 50% [IC50] of the high-affinity site, 7.7+/-0.15 and 7.9+/-0.27; -log IC50 of the low-affinity site = 5.6+/-0.44 and 5.3+/-0.28 [n = 4]).


CONCLUSIONS
These findings suggest that xinafoic acid, the solvent for salmeterol, does not have direct airway irritant effects, does not bind to beta-adrenoceptors, and does not impair the binding of salmeterol to beta-adrenoceptors. Thus, xinafoate is unlikely to contribute to the worsening of airway symptoms in asthmatics using salmeterol xinafoate.
Groeben
H
H
Abteilung für Anaesthesiologie & Intensivmedizin, Universität Essen, Germany. harald.groeben@uni-essen.de
Emala
C
C
D000280:Administration, Inhalation; D000403:Airway Resistance / Q000187:drug effects; D000420:Albuterol / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D016085:Bronchoconstrictor Agents / Q000008:administration & dosage; D001993:Bronchodilator Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004285:Dogs; D000431:Ethanol / Q000008:administration & dosage; D020120:Iodocyanopindolol / Q000378:metabolism; D016210:Methacholine Chloride / Q000008:administration & dosage; D009126:Muscle Relaxation / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009284:Naphthols / Q000494:pharmacology*; D009330:Nebulizers and Vaporizers; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D000068299:Salmeterol Xinafoate; D012997:Solvents
D016085:Bronchoconstrictor Agents; D001993:Bronchodilator Agents; D009284:Naphthols; D011943:Receptors, Adrenergic, beta; D012997:Solvents; D016210:Methacholine Chloride; D000431:Ethanol; D000068299:Salmeterol Xinafoate; D020120:Iodocyanopindolol; D000420:Albuterol; C050175:1-hydroxy-2-naphthoic acid