title: Positive interaction of the beta2-agonist CHF 4226.01 with budesonide in the control of bronchoconstriction induced by acetaldehyde in the guinea-pigs.
abstract: 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.
authors.affiliation: Department of Pharmacological Sciences, University of Milan, Milan, Italy, USA. giuseppe.rossoni@unimi.it
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Rossoni
authors.forename: Barbara
authors.initials: B
authors.lastname: Manfredi
authors.forename: Roberta
authors.initials: R
authors.lastname: Razzetti
authors.forename: Maurizio
authors.initials: M
authors.lastname: Civelli
authors.forename: Stefano
authors.initials: S
authors.lastname: Bongrani
authors.forename: Ferruccio
authors.initials: F
authors.lastname: Berti
mesh_terms: 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
chemical_list: 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