Synergistic effect of formoterol and mometasone in a mouse model of allergic lung inflammation.
OBJECTIVE
Controversy still exists as to whether or not inhaled beta (2)-adrenoceptor agonists and corticosteroids act synergistically in vivo. In this study, we have used a murine model of lung inflammation to study the synergistic effect of an inhaled beta (2)-adrenoceptor agonist (formoterol) and an inhaled corticosteroid (mometasone).


METHODS
Actively sensitized mice were challenged with aerosolized ovalbumin, once a day, for three consecutive days. Three days after the last of the three challenges, a final allergen challenge was given. Allergen-induced increase in Penh was measured 4 h after the last challenge. A day after the last challenge, increased airway sensitivity to aerosolized methacholine was demonstrated and this was concomitant with an influx of inflammatory cells in the bronchoalveolar lavage fluids.


RESULTS
Mometasone (0.1 to 3 mg kg(-1)) given intranasally either an hour before or after the last allergen challenge, dose-dependently inhibited all parameters. When given intranasally either one or three hours after the last allergen challenge, but not an hour before, formoterol (1.5 to 150 microg kg(-1)) also dose-dependently inhibited most of the parameters to different degree. A synergistic effect on the allergen-induced increase in Penh was demonstrated for mometasone and formoterol given in combination, an hour after the challenge, at the following doses: mometasone/formoterol (in microg kg(-1)) 1/10, 1/100, 5/10, and 5/100.


CONCLUSIONS
Our results support the hypothesis that when given as a fixed combination, inhaled corticosteroid and beta (2)-adrenoceptor agonist act synergistically in vivo.
Wyss
D
D
Respiratory Diseases Area, Novartis Institute for BioMedical Research, CH-4002 Basel, Switzerland.
Bonneau
O
O
Trifilieff
A
A
D000281:Administration, Intranasal; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D018926:Anti-Allergic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016085:Bronchoconstrictor Agents / Q000008:administration & dosage; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004357:Drug Synergism; D004983:Ethanolamines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D000068759:Formoterol Fumarate; D016210:Methacholine Chloride / Q000008:administration & dosage; D051379:Mice; D008807:Mice, Inbred BALB C; D000068656:Mometasone Furoate; D010047:Ovalbumin; D011244:Pregnadienediols / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D012129:Respiratory Function Tests; D012130:Respiratory Hypersensitivity / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors
D000318:Adrenergic beta-Agonists; D018926:Anti-Allergic Agents; D000893:Anti-Inflammatory Agents; D016085:Bronchoconstrictor Agents; D004338:Drug Combinations; D004983:Ethanolamines; D011244:Pregnadienediols; D000068656:Mometasone Furoate; D016210:Methacholine Chloride; D010047:Ovalbumin; D000068759:Formoterol Fumarate