Positive interaction of the beta2-agonist CHF 4226.01 with budesonide in the control of bronchoconstriction induced by acetaldehyde in the guinea-pigs.
Pretreatment of anaesthetized guinea-pigs with either CHF 4226.01 (8-hydroxy-5-[(1R)-1-hydroxy-2-[N-[(1R)-2-(p-methoxyphenyl)-1-methylethyl]amino]ethyl] carbostyril hydrochloride), formoterol or budesonide reduced acetaldehyde (AcCHO)-evoked responses in the lungs with a rank order of potency CHF 4226.01 (ED(50) values, from 1.88 to 3.31 pmol) > formoterol (ED(50) values, from 3.03 to 5.51 pmol) >> budesonide (ED(50) values, from 335 to 458 nmol). The duration of action of CHF 4226.01 in antagonizing the airway obstruction elicited by AcCHO was also substantially longer than formoterol (area under the curve) at 10 pmol, 763+/-58 and 480+/-34, respectively; P<0.01). Continuous infusion of a subthreshold dose of AcCHO enhanced the intratracheal pressure (ITP) increases caused by subsequent challenges with substance P (from 9.7+/-0.8 to 27.5+/-1.6 cm H(2)O as a peak, P<0.001). Pretreatment with either CHF 4226.01 or formoterol prevented the sensitizing effect of AcCHO on substance P responses (ED(50) values, 2.85 and 6.11 pmol, respectively; P<0.01). The ED(50) value of budesonide (396 nmol) in preventing AcCHO-evoked ITP increase was reduced when this glucocorticoid was combined with 0.1 pmol CHF 4226.01 (ED(50) 76 nmol; P<0.001). CHF 4226.01/budesonide was two-fold more effective (P<0.01) than the formoterol/budesonide combination. These results suggest that CHF 4226.01/budesonide, by optimizing each other's beneficial potential in the control of pulmonary changes caused by AcCHO in the guinea-pigs, may represent a new fixed combination in asthma.
Rossoni
Giuseppe
G
Department of Pharmacological Sciences, University of Milan, Milan, Italy, USA. giuseppe.rossoni@unimi.it
Manfredi
Barbara
B
Razzetti
Roberta
R
Civelli
Maurizio
M
Bongrani
Stefano
S
Berti
Ferruccio
F
D000079:Acetaldehyde / Q000494:pharmacology*; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000662:Amphetamines; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects*; D001993:Bronchodilator Agents / Q000494:pharmacology*; D019819:Budesonide / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004983:Ethanolamines / Q000494:pharmacology; D005021:Ethylamines / Q000494:pharmacology*; D000068759:Formoterol Fumarate; D006168:Guinea Pigs; D006632:Histamine / Q000097:blood; D006912:Hydroxyquinolines / Q000494:pharmacology*; D007293:Inosine Triphosphate / Q000494:pharmacology; D008297:Male; D015363:Quinolones; D013373:Substance P / Q000494:pharmacology
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D000662:Amphetamines; D001993:Bronchodilator Agents; D004983:Ethanolamines; D005021:Ethylamines; D006912:Hydroxyquinolines; D015363:Quinolones; D007293:Inosine Triphosphate; D013373:Substance P; D019819:Budesonide; D006632:Histamine; C074413:carmoterol; D000079:Acetaldehyde; D000068759:Formoterol Fumarate