Pharmacological assessment of the duration of action of glycopyrrolate vs tiotropium and ipratropium in guinea-pig and human airways.
1. Our study was aimed at investigating the duration of the bronchodilator action of the antimuscarinc drug glycopyrrolate compared to tiotropium and ipratropium. In the guinea-pig isolated trachea, the time (t1/2) necessary for a contractile response to carbachol (0.3 microM) to return to 50% recovery after washout of the antagonist was studied. The offset of the antagonist effect of glycopyrrolate, tiotropium and ipratropium (10 nM each) was t1/2 = 4.0 +/- 0.5, > 4.5 and 0.5 +/- 0.1 h, respectively. At 4.5 h from the washout of the antagonist, the recovery of the response to carbachol was 50 +/- 8, 10 +/- 4 and 70 +/- 7%, respectively. 2. In the human isolated bronchus, the offset of the bronchodilator effects of glycopyrrolate (3 nM), tiotropium (1 nM) and ipratropium (10 nM) was t1/2 = 3.7 +/- 0.2; > 6 and 3.0 +/- 0.2 h, respectively. At 6.0 h from the washout of the antagonist, the recovery of the response to carbachol (1 microM) was 101 +/- 10, 27 +/- 3 and 110 +/- 10%, respectively. 4. In anaesthetized guinea-pigs, acetylcholine-induced bronchoconstriction was markedly reduced by intratracheal instillation of glycopyrrolate (3 nmol kg(-1); 88.1 +/- 4% inhibition), tiotropium (1.3 nmol kg(-1); 86.2 +/- 5% inhibition) or ipratropium (1.45 nmol kg(-1); 88.1 +/- 10% inhibition). These inhibitory effects assessed 3 or 24 h after antagonist administration were reduced to 69.9 +/- 5 and 29.7 +/- 6%; 28.3 +/- 5 and 14.2 +/- 5% for glycopyrrolate and ipratropium, respectively, whereas they remained stable (83.5 +/- 4; 70.6 +/- 6) for tiotropium. The residual inhibitory effect of glycopyrrolate was also assessed at 16 h from administration, and proved to be as low as that found at 24 h (31.2 +/- 10 vs 29.7 +/- 6%, respectively). 5. In conclusion, glycopyrrolate-induced bronchodilation has a longer duration than that of ipratropium, but less than that of tiotropium. The efficacy of a possible glycopyrrolate-based therapy for asthma or chronic obstructive pulmonary disease given once-a-day is not guaranteed by the present investigation.
Villetti
Gino
G
Department of Pharmacology, Chiesi Farmaceutici SpA, Via Palermo 26-A, 43100 Parma, Italy.
Bergamaschi
Marco
M
Bassani
Franco
F
Bolzoni
Pier Tonino
PT
Harrison
Selena
S
Gigli
Paolo M
PM
Janni
Alberto
A
Geppetti
Pierangelo
P
Civelli
Maurizio
M
Patacchini
Riccardo
R
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001993:Bronchodilator Agents / Q000493:pharmacokinetics*; D006024:Glycopyrrolate / Q000493:pharmacokinetics; D006168:Guinea Pigs; D006801:Humans; D009241:Ipratropium / Q000493:pharmacokinetics; D018727:Muscarinic Antagonists / Q000493:pharmacokinetics*; D010599:Pharmacokinetics; D012137:Respiratory System / Q000187:drug effects*; D012602:Scopolamine Derivatives / Q000493:pharmacokinetics; D013997:Time Factors; D000069447:Tiotropium Bromide; D016896:Treatment Outcome
D001993:Bronchodilator Agents; D018727:Muscarinic Antagonists; D012602:Scopolamine Derivatives; D009241:Ipratropium; D000109:Acetylcholine; D006024:Glycopyrrolate; D000069447:Tiotropium Bromide