title: Ineffectiveness of a four week treatment with the thromboxane synthetase inhibitor, imidazole salycilate, in reducing airway hyperresponsiveness to methacholine in asthmatics.
abstract: In a randomized, double-blind, placebo-controlled study, the acute and long-term effects of the reduction of thromboxane A2 (TxA2) synthesis on airway sensitivity and maximal airway narrowing in response to methacholine was evaluated in 12 subjects with mild-to-moderate stable asthma, using imidazole salycilate (IS), an anti-inflammatory drug which selectively inhibits the TxA2 synthetase. Dose-response curves with methacholine (MCh) were performed in basal conditions (baseline); 1-1.5 h after administration of 1,500 mg of IS or placebo (acute); at 15 and 30 days of treatment with 750 mg t.i.d. of IS or placebo; and after a 2 week period of run-off (45 days). The serum levels of thromboxane B2 (TxB2) were measured at the same time points, except after acute administration, in five patients from each group. Baseline forced expiratory volume in one second (FEV1) was 78 +/- 7 and 85 +/- 8% of predicted in the IS and control group, respectively (NS). Throughout the study FEV1 remained unchanged in both groups, indicating that IS did not caused substantial modification of resting bronchial calibre. The initial provocative dose of methacholine causing a 20% fall in FEV1 (PD20) amounted to 27.0 +/- 1.5 micrograms in the IS group and 41.7 +/- 1.5 micrograms in the control group (geometric mean +/- GSEM) (NS). Despite a reduction of TxB2 serum levels with IS vs placebo at 15 days (24.9 +/- 8.5 vs 45.5 +/- 3.4 pg.mL-1; p < 0.05) and 30 days (27.0 +/- 6.3 vs 45.0 + 3.2 pg.mL-1; p < 0.05), MCh-induced bronchoconstriction, evaluated either as PD20 or maximal airway narrowing, did not change significantly during active treatment compared to placebo. These results show that prolonged reduction of thromboxane A2 synthesis does not improve airway sensitivity and limit maximal bronchoconstriction in asthmatic subjects, suggesting that thromboxane A2 per se does not play a substantial role in the pathogenesis of the airway hyperresponsiveness in human asthma.
authors.affiliation: Divisione di Medicina Interna of the Hospital of Gubbio, Perugia, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Peccini
authors.forename: M L
authors.initials: ML
authors.lastname: Dottorini
authors.forename: G
authors.initials: G
authors.lastname: Casucci
authors.forename: A M
authors.initials: AM
authors.lastname: Mezzasoma
authors.forename: C A
authors.initials: CA
authors.lastname: Sorbini
authors.forename: C
authors.initials: C
authors.lastname: Tantucci
mesh_terms: D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy / Q000503:physiopathology*; D016535:Bronchial Hyperreactivity / Q000188:drug therapy*; D001985:Bronchial Provocation Tests; D016085:Bronchoconstrictor Agents; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D016210:Methacholine Chloride; D008875:Middle Aged; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D017211:Treatment Failure
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016085:Bronchoconstrictor Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D016210:Methacholine Chloride; C029899:imidazole; D013930:Thromboxane-A Synthase