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THE INHALED MUSCARINIC RECEPTOR ANTAGONIST, GLYCOPYRROLATE, HAS A FAVORABLE SIDE EFFECT PROFILE IN A BROWN NORWAY RAT LUNG FUNCTION MODEL WHEN COMPARED WITH TIOTROPIUM

Novartis Institute for BioMedical Research, Basel, Switzerland

PURPOSE: Inhaled muscarinic receptor antagonists are recognised bronchodilator therapies for chronic obstructive pulmonary disease. However, the use of such drugs are associated with dry mouth at therapeutic doses and other anticholinergic systemic side effects have been noted at higher doses.. We describe a rat in vivo model that facilitates the concurrent assessment of potency, duration of action and potential for side effects of muscarinic receptor antagonists and have used this model to compare the muscarinic antagonists glycopyrrolate and tiotropium (a marketed inhaled muscarinic antagonist).

METHODS: Anaesthetised Brown Norway rats were intravenously injected with increasing doses of methacholine and changes in airway resistance, salivation, blood pressure and heart rate were recorded. Drugs were given intratracheally, as a solution, 1, 6 or 24 hours before the start of the methacholine sequence.

RESULTS: Intravenous injection of methacholine, to anaesthetised rats, induced bronchoconstriction, salivation, hypotension and tachycardia with ED50 values of 15.7 ± 4.6, 10.1 ± 4.7, 2.9 ± 0.6 and 45.9 ± 24.2 µg/kg, respectively. Glycopyrrolate and tiotropium inhibited the methacholine-induced bronchoconstriction for up to 24 hours post dosing, at which time point their respective ED50 values, against 30 µg/kg of methacholine, were 1.33 ± 0.56 and 0.17 ± 0.08 µg/kg. When compared with tiotropium and at all the time points studied, glycopyrrolate had reduced potential to effect the salivation and cardiovascular parameters when compared to the bronchoprotective.

CONCLUSION: When given locally to the lung of rats, glycopyrrolate has a duration of action compatible with once daily dosing and shows a reduced potential for systemic side effects when compared to tiotropium.

CLINICAL IMPLICATIONS: Our data support the development of glycopyrrolate as a once daily inhaled muscarinic antagonist and suggest that this compound has the potential for lower cardiovascular side effects and reduced dry mouth when compared with tiotropium.

DISCLOSURE: Alexandre Trifilieff, No Product/Research Disclosure Information; Other All authors are or have been employee of Novartis AG. Novartis AG is developping an inhaled formulation of glycopyrrolate.